Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonists

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/718,760, filed Apr. 12, 2022, pending, which a continuation of U.S.patent application Ser. No. 17/221,859, filed Apr. 5, 2021, abandoned,which is a continuation of U.S. patent application Ser. No. 16/732,387,filed Jauanry 02, 2020, now U.S. Pat. No. 11,007,180, issued May 18,2021, which is a divisional application of U.S. patent application Ser.No. 16/038,739, filed Jul. 18, 2018, now U.S. Pat. No. 10,576,062,issued Mar. 3, 2020, which is a divisional application of U.S. patentapplication Ser. No. 15/628,104, filed on Jun. 20, 2017, now U.S. Pat.No. 10,071,078, issued Sep. 11, 2018, which claims priority to U.S.Provisional Application Ser. No. 62/352,792, filed Jun. 21, 2016, theentire content of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel substituted triazole compounds,compositions containing them, and methods of using them, for example,for the treatment or prophylaxis of disorders associated with one ormore of the lysophosphatidic acid (LPA) receptors.

BACKGROUND OF THE INVENTION

Lysophospholipids are membrane-derived bioactive lipid mediators, ofwhich one of the most medically important is lysophosphatidic acid(LPA). LPA is not a single molecular entity but a collection ofendogenous structural variants with fatty acids of varied lengths anddegrees of saturation (Fujiwara et al., J Biol. Chem., 2005, 280,35038-35050). The structural backbone of the LPAs is derived fromglycerol-based phospholipids such as phosphatidylcholine (PC) orphosphatidic acid (PA).

The LPAs are bioactive lipids (signaling lipids) that regulate variouscellular signaling pathways by binding to the same class of7-transmembrane domain G protein-coupled (GPCR) receptors (Chun, J.,Hla, T., Spiegel, S., Moolenaar, W., Editors, LysophospholipidReceptors: Signaling and Biochemistry, 2013, Wiley; IS 13 N:978-O-470-56905-4 & Zhao, Y. et al. Biochem. Biophys. Acta (BBA)-Mol.Cell Biol. Of Lipids, 2013, 1831, 86-92). The currently known LPAreceptors are designated as LPA1, LPA2, LPA3, LPA4, LPA5 and LPA6 (Choi,J. W., Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186).

The LPAs have long been known as precursors of phospholipid biosynthesisin both eukaryotic and prokaryotic cells, but the LPAs have emerged onlyrecently as signaling molecules that are rapidly produced and releasedby activated cells, notably platelets, to influence target cells byacting on specific cell-surface receptors (see, e.g., Moolenaar et al.,BioEssays, 2004, 26, 870-881, and van Leewen et al., Biochem. Soc.Trans., 2003, 31, 1209-1212). Besides being synthesized and processed tomore complex phospholipids in the endoplasmic reticulum, LPAs can begenerated through the hydrolysis of pre-existing phospholipids followingcell activation; for example, the sn-2 position is commonly missing afatty acid residue due to deacylation, leaving only the sn-1 hydroxylesterified to a fatty acid. Moreover, a key enzyme in the production ofLPA, autotaxin (lysoPLD/NPP2), may be the product of an oncogene, asmany tumor types up-regulate autotaxin (Brindley, D., J. Cell Biochem.2004, 92, 900-12). The concentrations of LPAs in human plasma & serum aswell as human bronchoalveolar lavage fluid (BALF) have been reported,including determinations made using sensitive and specific LC/MS &LC/MS/MS procedures (Baker et al. Anal. Biochem., 2001, 292, 287-295;Onorato et al., J. Lipid Res., 2014, 55, 1784-1796).

LPA influences a wide range of biological responses, ranging frominduction of cell proliferation, stimulation of cell migration andneurite retraction, gap junction closure, and even slime mold chemotaxis(Goetzl, et al., Scientific World J., 2002, 2, 324-338; Chun, J., Hla,T., Spiegel, S., Moolenaar, W., Editors, Lysophospholipid Receptors:Signaling and Biochemistry, 2013, Wiley; ISBN: 978-O-470-56905-4). Thebody of knowledge about the biology of LPA continues to grow as more andmore cellular systems are tested for LPA responsiveness. For instance,it is now known that, in addition to stimulating cell growth andproliferation, LPAs promote cellular tension and cell-surfacefibronectin binding, which are important events in wound repair andregeneration (Moolenaar et al., BioEssays, 2004, 26, 870-881). Recently,anti-apoptotic activity has also been ascribed to LPA, and it hasrecently been reported that PPARγ is a receptor/target for LPA (Simon etal., J. Biol. Chem., 2005, 280, 14656-14662).

Fibrosis is the result of an uncontrolled tissue healing process leadingto excessive accumulation and insufficient resorption of extracellularmatrix (ECM) which ultimately results in end-organ failure (Rockey, D.C., et al., New Engl. J. Med., 2015, 372, 1138-1149). Recently it wasreported that the LPA1 receptor was over-expressed in idiopathicpulmonary fibrosis (IPF) patients. LPA1 receptor knockout mice were alsoprotected from bleomycin-induced lung fibrosis (Tager et al., NatureMed., 2008, 14, 45-54).

Thus, antagonizing the LPA1 receptor may be useful for the treatment offibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis,arterial fibrosis and systemic sclerosis, and thus the diseases thatresult from fibrosis (pulmonary fibrosis-Idiopathic Pulmonary Fibrosis[IPF], hepatic fibrosis-Non-alcoholic Steatohepatitis [NASH], renalfibrosis-diabetic nephropathy, systemic sclerosis-scleroderma, etc.)

SUMMARY OF THE INVENTION

The present invention provides novel substituted triazole compoundsincluding stereoisomers, tautomers, pharmaceutically acceptable salts,solvates or prodrugs thereof, which are useful as antagonists againstone or more of the lysophosphatidic acid (LPA) receptors, especially theLPA1 receptor.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates or prodrugs thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of conditions in which LPA plays a role.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a condition inwhich inhibition of the physiological activity of LPA is useful, such asdiseases in which an LPA receptor participates, is involved in theetiology or pathology of the disease, or is otherwise associated with atleast one symptom of the disease.

In another aspect, the present invention is directed to a method oftreating fibrosis of organs (liver, kidney, lung, heart and the like aswell as skin), liver diseases (acute hepatitis, chronic hepatitis, liverfibrosis, liver cirrhosis, portal hypertension, regenerative failure,non-alcoholic steatohepatitis (NASH), liver hypofunction, hepatic bloodflow disorder, and the like), cell proliferative disease [cancer (solidtumor, solid tumor metastasis, vascular fibroma, myeloma, multiplemyeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)and the like) and invasive metastasis of cancer cell, and the like],inflammatory disease (psoriasis, nephropathy, pneumonia and the like),gastrointestinal tract disease (irritable bowel syndrome (IBS),inflammatory bowel disease (IBD), abnormal pancreatic secretion, and thelike), renal disease, urinary tract-associated disease (benign prostatichyperplasia or symptoms associated with neuropathic bladder disease,spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis,symptoms derived from diabetes, lower urinary tract disease (obstructionof lower urinary tract, and the like), inflammatory disease of lowerurinary tract, dysuria, frequent urination, and the like), pancreasdisease, abnormal angiogenesis-associated disease (arterial obstructionand the like), scleroderma, brain-associated disease (cerebralinfarction, cerebral hemorrhage, and the like), neuropathic pain,peripheral neuropathy, and the like, ocular disease (age-related maculardegeneration (AMD), diabetic retinopathy, proliferativevitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtrationsurgery scarring, and the like).

In another aspect, the present invention is directed to a method oftreating diseases, disorders, or conditions in which activation of atleast one LPA receptor by LPA contributes to the symptomology orprogression of the disease, disorder or condition. These diseases,disorders, or conditions may arise from one or more of a genetic,iatrogenic, immunological, infectious, metabolic, oncological, toxic,surgical, and/or traumatic etiology.

In another aspect, the present invention is directed to a method oftreating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterialfibrosis and systemic sclerosis comprising administering to a patient inneed of such treatment a compound of the present invention as describedabove.

In one aspect, the present invention provides methods, compounds,pharmaceutical compositions, and medicaments described herein thatcomprise antagonists of LPA receptors, especially antagonists of LPA1.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In one aspect, the present invention provides, inter alia, compounds ofFormula

-   -   or stereoisomers, tautomers, pharmaceutically acceptable salts,        solvates or prodrugs thereof, wherein    -   R₂ is independently selected from H and C₁₋₄ alkyl substituted        with 1-5 R₉;    -   R₁₃ is independently selected from H, D, and C₁₋₄ alkyl        substituted with 1-3 R₉;    -   R₃ and R₄ are independently selected from H, C₁₋₇ alkyl        substituted with 1-3 R₉, —(CR₇R₇)_(r)—C₃₋₈ cycloalkyl        substituted with 1-3 R₈, —(CR₇R₇)_(r)-aryl substituted with 1-3        R₈, C₂₋₇alkenyl substituted with 1-3 R₉, —(CR₇R₇)_(r)-5-6        membered heterocyclic ring substituted with 1-3 R₈,        —(CR₇R₇)_(r)-5-6 membered heteroaryl ring substituted with 1-3        R₈, or R₃ and    -   R₄ combine with the N to which they are attached to form a 4-9        membered heterocyclic ring substituted with 1-3 R₈;    -   X¹, X², X³, and X⁴ are independently selected from CR₅ and N;        provided no more than two of X¹, X², X³, or X⁴ are N;    -   R₅ is independently selected from H, F, Cl, OR₇, CN, N(R₇)₂,        C₁₋₄ alkyl substituted with 1-5 R₉, C₁₋₄ alkoxy substituted with        1-5 R₉, and C₁₋₄ heteroalkyl substituted with 1-5 R₉;    -   R₆ is C₃₋₈ cycloalkyl which is substituted with R₁₀ and        (—CH₂)₀₋₁R₁₁;    -   R₇ is independently selected from H, C₁₋₄ alkyl, and C₃₋₆        cycloalkyl; or R₇ and R₇, together with the carbon atom to which        they both attach, form a C₃₋₆ cycloalkyl ring;    -   R₈ is independently selected from H, D, C₁₋₆ alkyl substituted        with 1-5 R₉, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, —(CH₂)_(r)—C₃₋₆        cycloalkyl, F, Cl, Br, CN, COOH, and C₁₋₄ alkoxy;    -   R₉ is independently selected from H, D, F, C₁, NH₂, OH,        OC₁₋₅alkyl, C₁₋₅alkyl, C₁₋₅ heteroalkyl C₃₋₆ cycloalkyl, and        phenyl, wherein when R₉ is Cl, NH₂ or OH it is not substituted        on C₁ of the the alkyl to which it is attached;    -   R₁₀ is independently selected from H, D, C₁₋₄ alkyl, F, Cl, Br,        OR₇, NHC(═O)OR₇, and NHC(═O)OR₇;    -   R₁₁ is independently selected from H, CN, —C(═O)R₁₂, tetrazolyl,

-   -   R₁₂ is independently selected from OH, OC₁₋₄ alkyl, NH₂,        NHCH₂CH₂SO₃H, and NHSO₂C₁₋₄alkyl;    -   r is independently selected from zero, 1, 2, 3, and 4,    -   and n is selected from 1, 2, 3, or 4.

In another embodiment, the present invention includes compounds ofFormula (I), wherein

-   -   R₃ and R₄ are independently selected from H, C₁₋₇ alkyl        substituted with 1-3 R₉, —(CR₇R₇)_(r)—C₃₋₈ cycloalkyl        substituted with 1-3 R₈, —(CR₇R₇)_(r)-aryl substituted with 1-3        R₈, C₂₋₇alkenyl substituted with 1-3 R₉, —(CR₇R₇)_(r)-5-6        membered heterocyclic ring substituted with 1-3 R₈,        —(CR₇R₇)_(r)-5-6 membered heteroaryl ring substituted with 1-3        R₈, and R₃ and R₄ combine with the N to which they are attached        to form the following:

each of which may be substituted with 1-3 R₈, and

-   -   n equals 1 or 2.

In another embodiment, the present invention includes compounds ofFormula (I) wherein, R₃ and R₄ are independently selected from H, C₁₋₇alkyl substituted with 1-3 R₉, —(CR₇R₇)_(r)—C₃₋₈ cycloalkyl substitutedwith 1-3 R₈, —(CR₇R₇)_(r)-aryl substituted with 1-3 R₈, C₂₋₇alkenylsubstituted with 1-3 R₉,

-   -   each of which can be substituted with 1-3 R₈, and R₃ and R₄        combine with the N to which they are attached to form a 4-9        membered heterocyclic ring substituted with 1-3 R₈; and n equals        1 or 2.

In another embodiment, the present invention includes compounds ofFormula

-   -   or stereoisomers, tautomers, pharmaceutically acceptable salts,        solvates, or prodrugs thereof, wherein    -   R₂ is independently selected from H and C₁₋₄ alkyl substituted        with 1-5 R₉;    -   R₁₃ is independently selected from H, D, and C₁₋₄ alkyl        substituted with 1-3 R₉;    -   R₃ and R₄ are independently selected from H, C₁₋₇ alkyl        substituted with 1-3 R₉, —(CR₇R₇)_(r)—C₃₋₆ cycloalkyl        substituted with 1-3 R₈, and —(CR₇R₇)_(r)-aryl substituted with        1-3 R₈;    -   X¹, X², X³, and X⁴ are independently selected from CR₅ and N;        provided no more than two of X¹, X², X³, or X⁴ are N;    -   R₅ is independently selected from H, F, Cl, OR₇, CN, N(R₇)₂,        C₁₋₄ alkyl substituted with 1-5 R₉, C₁₋₄ alkoxy substituted with        1-5 R₉, and C₁₋₄ heteroalkyl substituted with 1-5 R₉;    -   R₆ is

-   -   R₇ is independently selected from H, C₁₋₄ alkyl, and C₃₋₆        cycloalkyl; or R₇ and R₇, together with the carbon atom to which        they both attach, form a C₃₋₆ cycloalkyl ring;    -   R₈ is independently selected from H, C₁₋₆ alkyl substituted with        1-5 R₉, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(r)—C₃₋₆ cycloalkyl,        F, Cl, Br, CN, ═O, and CO₂H;    -   R₉ is independently selected from H, F, Cl, NH₂, OH, OC₁₋₅alkyl,        C₁₋₅alkyl, C₁₋₅ heteroalkyl C₃₋₆ cycloalkyl, and phenyl, wherein        when R₉ is Cl, NH₂ or OH it is not substituted on C₁ of the the        alkyl to which it is attached;    -   R₁₀ is independently selected from H, D, C₁₋₄ alkyl, F, Cl, Br,        OR₇, NHC(═O)OR₇, and NHC(═O)R₇;    -   R₁₁ is independently selected from CN, —C(═O)R₁₂, tetrazolyl,

-   -   R₁₂ is independently selected from OH, OC₁₋₄ alkyl, NH₂,        NHCH₂CH₂SO₃H, and NHSO₂C₁₋₄alkyl; and    -   r is independently selected from zero, 1, 2, 3, and 4.

In another aspect, the present invention provides compounds of Formula(III):

-   -   or stereoisomers, tautomers, pharmaceutically acceptable salts,        solvates, or prodrugs thereof, wherein    -   R₂ is independently selected from CH₃ and CD₃;    -   R₁₃ is independently selected from H and C₁₋₄ alkyl;    -   R₃ is independently selected from H and C₁₋₄ alkyl;    -   R₄ is independently selected from C₁₋₆ alkyl substituted with        1-3 R₉, —(CR₇R₇)_(r)—C₃₋₆ cycloalkyl substituted with 1-3 R₈,        and —(CR₇R₇)_(r)-aryl substituted with 1-3 R₈;    -   R₅ is independently selected from H, F, Cl, CN and C₁₋₄ alkyl;        provided one of R₅ is H;    -   R₆ is

-   -   R₇ is independently selected from H, C₁₋₄ alkyl, and C₃₋₆        cycloalkyl; or R₇ and R₇, together with the carbon atom to which        they both attach, form a C₃₋₆ cycloalkyl ring;    -   R₈ is independently selected from H, C₁₋₆ alkyl substituted with        1-5 R₉, C₃₋₆ cycloalkyl, F, Cl, Br, CN, ═O, and COOH;    -   R₉ is independently selected from H, F, Cl, NH₂, OH, OC₁₋₅alkyl,        C₁₋₅alkyl, C₃₋₆ cycloalkyl, and phenyl, wherein when R₉ is Cl,        NH₂ or OH it is not substituted on C₁ of the the alkyl to which        it is attached;    -   R₁₀ is independently selected from H, D, C₁₋₄ alkyl, and F;    -   R₁₁ is independently selected from CN, —C(═O)R₁₂, and        tetrazolyl;    -   R₁₂ is independently selected from OH, OC₁₋₄ alkyl, NH₂, and        NHSO₂C₁₋₄alkyl; and    -   r is independently selected from zero, 1, 2, 3, and 4.

In another aspect, the present invention provides compounds of Formula(IV):

-   -   or stereoisomers, tautomers, pharmaceutically acceptable salts,        solvates, or prodrugs thereof, wherein    -   R₂ is independently selected from CH₃ and CD₃;    -   R₁₃ is independently selected from H and C₁₋₄ alkyl;    -   R₃ is independently selected from H and C₁₋₄ alkyl;    -   R₄ is independently selected from C₁₋₆ alkyl,

-   -   R₅ is independently selected from H, F, Cl, and C₁₋₄ alkyl;        provided one of R₅ is H;    -   R₇ is independently selected from H, C₁₋₄ alkyl, and C₃₋₆        cycloalkyl;    -   R₈ is independently selected from H, C₁₋₆ alkyl substituted with        1-5 R₉, C₃₋₆ cycloalkyl, F, Cl, Br, CN, ═O, and COOH;    -   R₉ is independently selected from H, F, Cl, NH₂, OH, OC₁₋₅alkyl,        C₁₋₅alkyl, C₃₋₆ cycloalkyl, and phenyl, wherein when R₉ is Cl,        NH₂ or OH it is not substituted on C₁ of the the alkyl to which        it is attached;    -   R₁₀ is independently selected from H, D, C₁₋₄ alkyl, and F;    -   R₁₁ is independently selected from CN, —C(═O)R₁₂,

-   -    and    -   R₁₂ is independently selected from OH, NH₂ and NHSO₂C₁₋₄alkyl.

In another aspect, the present invention provides compounds of Formula(III) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein

-   -   R₄ is independently selected from

and

-   -   R₈ is independently selected from H, F, Cl, Br, CN, and C₁₋₄        alkyl; and other variables are as defined in Formula (IV).

In another aspect, the present invention provides compounds of Formula(V):

-   -   or stereoisomers, tautomers, pharmaceutically acceptable salts,        solvates, or prodrugs thereof, wherein    -   R₂ is independently selected from CH₃ and CD₃;    -   R₁₃ is independently selected from H and CH₃;    -   R₃ is independently selected from H and CH₃;    -   R₄ is independently selected from

and

-   -   R₅ is independently selected from H, F, and C₁₋₄ alkyl;    -   R₈ is independently selected from H, F, Cl, Br, CN, and C₁₋₄        alkyl;    -   R₁₀ is independently selected from H, D, and F; and    -   R₁₁ is independently selected from —C(═O)OH, and —C(═O)NHSO₂Me.

In another aspect, the present invention provides compounds of Formula(VI):

-   -   or stereoisomers, tautomers, pharmaceutically acceptable salts,        solvates, or prodrugs thereof, wherein    -   R₂ is independently selected from CH₃ and CD₃;    -   R₁₃ is independently selected from H and CH₃;    -   R₃ is independently selected from H and CH₃;    -   R₄ is independently selected from

-   -   R₅ is independently selected from H and CH₃; and    -   R₈ is independently selected from H, F, Cl, Br, CN, and C₁₋₄        alkyl.

In another aspect, the present invention provides compounds of Formula(VII):

-   -   or stereoisomers, tautomers, pharmaceutically acceptable salts,        solvates, or prodrugs thereof, wherein    -   R₂ is independently selected from CH₃ and CD₃;    -   R₁₃ is independently selected from H and C₁₋₄ alkyl;    -   R₃ is independently selected from H and C₁₋₄ alkyl;    -   R₄ is independently selected from C₁₋₆ alkyl substituted with        1-3 R₉, (CR₇R₇)_(r)—C₃₋₆ cycloalkyl substituted with 1-3 R₈, and        —(CR₇R₇)_(r)-aryl substituted with 1-3 R₈;    -   R₅ is independently selected from H, F, Cl, CN, and C₁₋₄ alkyl;    -   R₆ is

-   -   R₇ is independently selected from H, C₁₋₄ alkyl, and C₃₋₆        cycloalkyl; or R₇ and R₇, together with the carbon atom to which        they both attach, form a C₃₋₆ cycloalkyl ring;    -   R₈ is independently selected from H, C₁₋₆ alkyl substituted with        1-5 R₉, C₃₋₆ cycloalkyl, F, Cl, Br, CN, ═O, and COOH;    -   R₉ is independently selected from H, F, Cl, NH₂, OH, OC₁₋₅alkyl,        C₁₋₅alkyl, C₃₋₆ cycloalkyl, and phenyl, wherein when R₉ is Cl,        NH₂ or OH it is not substituted on C₁ of the the alkyl to which        it is attached;    -   R₁₀ is independently selected from H, C₁₋₄ alkyl, and F;    -   R₁₁ is independently selected from CN, —C(═O)R₁₂, tetrazolyl,

-   -   R₁₂ is independently selected from OH, OC₁₋₄ alkyl, NH₂,        NHCH₂CH₂SO₃H, and NHSO₂C₁₋₄alkyl; and    -   r is independently selected from zero, 1, 2, 3, and 4.

In another aspect, the present invention provides compounds of Formula(VI) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein

-   -   R₁ is independently selected from CH₃ and CD₃;    -   R₂ is independently selected from H and CH₃;    -   R₃ is independently selected from H and CH₃;    -   R₄ is independently selected from C₁₋₆ alkyl,

-   -   R₅ is independently selected from H, F, Cl, and C₁₋₄ alkyl;    -   R₆ is

-   -   R₇ is independently selected from H, C₁₋₄ alkyl, and C₁₋₆        cycloalkyl; and    -   R₈ is independently selected from H, F, Cl, Br, CN, and C₁₋₄        alkyl.

In another aspect, the present invention provides compounds of Formula(VIII):

-   -   or stereoisomers, tautomers, pharmaceutically acceptable salts,        solvates, or prodrugs thereof, wherein    -   R₂ is independently selected from CH₃ and CD₃;    -   R₁₃ is independently selected from H and CH₃;    -   R₃ is independently selected from H and CH₃;    -   R₄ is independently selected from

-   -   R₅ is independently selected from H, F, and CH₃; and    -   R₈ is independently selected from H, F, Cl, Br, CN, and C₁₋₄        alkyl.

In another aspect, the present invention provides compounds of Formula(IX):

-   -   or stereoisomers, tautomers, pharmaceutically acceptable salts,        solvates, or prodrugs thereof, wherein    -   R₂ is independently selected from CH₃ and CD₃;    -   R₁₃ is independently selected from H and C₁₋₄ alkyl;    -   R₃ is independently selected from H and C₁₋₄ alkyl;    -   R₄ is independently selected from C₁₋₆ alkyl substituted with        1-3 R₉, (CR₇R₇)_(r)—C₃₋₆ cycloalkyl substituted with 1-3 R₈, and        —(CR₇R₇)_(r)-aryl substituted with 1-3 R₈;    -   R₈ is independently selected from H, F, CN, and C₁₋₄ alkyl;    -   R₆ is independently selected from

-   -   R₇ is independently selected from H, C₁₋₄ alkyl, and C₃₋₆        cycloalkyl; or R₇ and R₇, together with the carbon atom to which        they both attach, form a C₃₋₆ cycloalkyl ring;    -   R₈ is independently selected from H, C₁₋₆ alkyl substituted with        1-5 R₉, C₃₋₆ cycloalkyl, F, Cl, Br, CN, ═O, and COOH;    -   R₉ is independently selected from H, F, Cl, NH₂, OH, OC₁₋₅alkyl,        C₁₋₅alkyl, C₃₋₆ cycloalkyl, and phenyl, wherein when R₉ is Cl,        NH₂ or OH it is not substituted on C₁ of the the alkyl to which        it is attached;    -   R₁₀ is independently selected from H, and F,    -   R₁₁ is independently selected from CN, —C(═O)R₁₂, tetrazolyl,

-   -   R₁₂ is independently selected from OH, OC₁₋₄ alkyl, NH₂,        NHCH₂CH₂SO₃H, and NHSO₂C₁₋₄alkyl; and    -   r is independently selected from zero, 1, 2, 3, and 4.

In yet another embodiment, the present invention includes a compound ofFormula (I) or (II) selected from the group of:

or an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes a compound ofFormula (I) or (II) selected from the group of:

or an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

or an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the present invention includes compound ofFormula (I) or (II) wherein said compound has the formula:

an enantiomer, a diastereomer, a stereoisomer, or a pharmaceuticallyacceptable salt thereof.

For any and all of the embodiments, substituents are selected from amongfrom a subset of the listed alternatives. For example, in someembodiments, R₁₂ is —OH, —OC₁₋₄ alkyl, or —NHSO₂C₁₋₄ alkyl. In someembodiments, R₁₂ is —OH or —OC₁₋₄ alkyl. In some embodiments, R₁₂ is—OH. In some embodiments, R₁₂ is —OC₁₋₄ alkyl. In some embodiments, R₁₂is —OCH₃ or —OCH₂CH₃. In some embodiments, R₁₂ is —NHSO₂C₁₋₄alkyl.

In some embodiments, R₃ is C₁₋₄ alkyl; R₅ is H or C₁₋₄ alkyl. In someembodiments, R₁₂ is —OH, —OCH₃, —OCH₂CH₃, —NHSO₂CH₃ or —NHSO₂CH₂CH₃; R₃is —CH₃, CD₃ or —CH₂CH₃. In some embodiments, R₁₂ is —OH, —OCH₃,—OCH₂CH₃, —NHSO₂CH₃ or —NHSO₂CH₂CH₃; R₃ is —CH₃, CD₃, or —CH₂CH₃; R₅ isH or C₁₋₄ alkyl.

In some embodiments, R₄ is

wherein

is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 2-deuteromethylphenyl,3-deuteromethylphenyl, 4-deuteromethylphenyl, 2-monofluoromethylphenyl,3-monofluoromethylphenyl, 4-monofluoromethylphenyl,2-difluoromethylphenyl, 3-difluoromethylphenyl, 4-difluoromethylphenyl,2-cyclopropylphenyl, 3-cyclopropylphenyl, 4-cyclopropylphenyl,2-cyclobutylphenyl, 3-cyclobutylphenyl, 4-cyclobutylphenyl,2-cyclopentylphenyl, 3-cyclopentylphenyl, 4-cyclopentylphenyl,2-cyclohexylphenyl, 3-cyclohexylphenyl or 4-cyclohexylphenyl.

In some embodiments, R₄ is —(CHR₇)_(r)—C₃₋₆ cycloalkyl and r is 0, 1, or2, and R₇ is H or methyl. In some embodiments, r is 0, R₄ iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and R₇ is H ormethyl. In some embodiments, r is 1, R₄ is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, R₇ is H or methyl.

In some embodiments, R₃ is C₁₋₄ alkyl, R₄ is —(CHR₇)_(r)—C₃₋₆cycloalkyl, and r is 0, 1, or 2, and R₇ is H or methyl. In someembodiments, R₃ is —CH₃, CD₃, or —CH₂CH₃, R₄ is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, r is 0 or 1, and R₇ is H or methyl. In someembodiments, R₃ is —CH₃, R₄ is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, r is 1, R₇ is H or methyl.

In some embodiments, R₃ is C₁₋₄ alkyl, R₄ is C₁₋₄ alkyl, and R₇ is H ormethyl. In some embodiments, R₃ is —CH₃, CD₃, or —CH₂CH₃, R₄ is —CH₃,CD₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, or—CH(CH₃)₃, and R₇ is H or methyl. In some embodiments, R₃ is —CH₃, R₄ is—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, or—CH(CH₃)₃, R₇ is H or methyl.

In some embodiments, R₁ is H or C₁₋₂ alkyl, R₂ is H or C₁₋₂ alkyl, R₃ isC₁₋₂ alkyl, R₄ is —(CHR₇)_(r)—C₃₋₆ cycloalkyl and r is 1, R₅ is H orC₁₋₂ alkyl, R₆ is cyclopentyl or cyclohexyl, R₇ is H or C₁₋₂ alkyl, R₈is H, R₉ is H, R₁₀ is H, and R₁₁ is —C(═O)OH.

In some embodiments, R₁ is H or methyl, R₂ is H or methyl, R₃ is methyl,R₄ is —CHR₇-cyclopropyl, —CHR₇-cyclobutyl, —CHR₇-cyclopentyl, or—CHR₇-cyclohexyl, R₅ is H or methyl, R₆ is cyclohexyl, R₇ is H ormethyl, R₈ is H, R₉ is H, R₁₀ is H, and R₁ is —C(═O)OH.

In some embodiments, the pharmaceutically acceptable salt of thecompound of Formulas (I)-(IX) is a sodium salt.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds exemplified in the presentapplication.

In another embodiment, the present invention includes compounds ofFormula (X):

-   -   or an enantiomer, a diastereomer, or a stereoisomer thereof,        wherein    -   R₂₀ is independently selected from C₁₋₆ alkyl or H;    -   R₂₁ is independently selected from C₁₋₆ alkyl or H;    -   X⁵ and X⁶ are independently selected from CH or N; and    -   X⁷ is selected from Cl, Br, or F.

In another embodiment, the present invention includes compounds ofFormula (XI):

or an enantiomer, a diastereomer, or a stereoisomer thereof.

In another aspect, the present invention provides a compound selectedfrom the list below:

-   (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (1)-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (2)-   (1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (3)-   trans-3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (4)-   (1S,3S)-3-(4-(5-(((Cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic    acid (5)-   (1R,3R)-3-(4-(5-(((Cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic    acid (6)-   (1-Methyl-4-(4-(((1S,3S)-3-((methylsulfonyl)carbamoyl)cyclohexyl)oxy)phenyl)-1H-1,2,3-triazol-5-yl)methyl    cyclopentyl(methyl)carbamate (7)

No names for (8) and (9)

-   (1S,3S)-3-(4-(1-Methyl-5-(((methyl(2-methylpentan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic    acid (10)-   3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic    acid (11)-   (1S,3S)-3-(4-(5-(1-(((cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (12)-   3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic    acid (13)-   (4-(5-(((1S,3S)-3-carbamoylcyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl    (cyclobutylmethyl)(methyl)carbamate (14)-   (4-(5-(((1S,3S)-3-cyanocyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl    (cyclobutylmethyl)(methyl)carbamate (15)-   (4-(5-(((1S,3S)-3-(1H-tetrazol-5-yl)cyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl    (cyclobutylmethyl)(methyl)carbamate (16)-   (1-methyl-4-(6-methyl-5-(((1S,3S)-3-((methylsulfonyl)carbamoyl)    cyclohexyl)oxy)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)methyl    (cyclobutylmethyl)(methyl)carbamate (17)-   3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (18),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((R)-1-phenylethyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (19),-   (1S,3S)-3-((6-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (20),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl((R)-1-phenylethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (21),-   (1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (22),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (23),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (24),-   (1S,3S)-3-((6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (25),-   (1S,3S)-3-(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic    acid (26),-   (1S,3S)-3-(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic    acid (27),-   (1S,3S)-3-(2-fluoro-4-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (28),-   (1S,3S)-3-((6-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (29),-   (1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (30),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (31),-   (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (32),-   (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (33),-   (1S,3S)-3-((6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (34),-   (1S,3S)-3-((6-(5-((((4-chlorobenzyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (35),-   (1S,3S)-3-(4-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic    acid (36),-   (1S,3S)-3-(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic    acid (37),-   (1S,3S)-3-(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic    acid (38),-   (1S,3S)-3-(2-methyl-4-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid    (39),-   (1S,3S)-3-(4-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic    acid (40),-   (1S,3S)-3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic    acid (41),-   (1S,3S)-3-((6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-4-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (42),-   (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (43),-   (1S,3S)-3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic    acid (44),-   (1S,3S)-3-(4-(5-((((1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic    acid (45),-   (1S,3S)-3-(4-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic    acid (46),-   (1S,3S)-3-(2-fluoro-4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (47),-   (1S,3S)-3-(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (isomer 1) (48),-   (1S,3S)-3-(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (isomer 2) (49),-   (1S,3S)-3-((6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (50),-   (1S,3S)-3-(4-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (51),-   (1S,3S)-3-(4-(5-(((((S)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (52),-   (1S,3S)-3-(4-(5-(((isobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (53),-   (1S,3S)-3-(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (54),-   (1S,3S)-3-(4-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (55),-   (1S,3S)-3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic    acid (56),-   (1S,3S)-3-(4-(1-methyl-5-(((methyl(pentan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (57),-   (1S,3S)-3-(4-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (58),-   (1S,3S)-3-(4-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (59),-   (1S,3S)-3-(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (60),-   (1S,3S)-3-(4-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (61),-   (1R,3R)-3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (62),-   (1R,3R)-3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic    acid (63),-   (1S,3S)-3-(4-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (64),-   (1S,3S)-3-(4-(5-((((1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (65),-   (1S,3S)-3-(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (66),-   (1S,3S)-3-(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (67),-   (1S,3S)-3-(4-(5-(((sec-butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (68),-   (3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic-1-d    acid (69),-   (1S,3S)-3-(4-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane-1-carboxylic    acid (70),-   (1S,3S)-3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (71),-   (1-Methyl-4-(4-(((1R,3R)-3-((methylsulfonyl)carbamoyl)cyclohexyl)oxy)phenyl)-1H-1,2,3-triazol-5-yl)methyl    cyclopentyl(methyl)carbamate (72),-   (1S,3S)-3-(4-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (73),-   (1S,3S)-3-(4-(5-((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylic    acid (74),-   (1S,3S)-3-(4-(1-methyl-5-(((methyl(1-propylcyclopropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (75),-   (1S,3S)-3-(4-(1-methyl-5-(((methyl(pentan-3-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (76),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(pentan-3-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (77),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(2-methylpentan-2-yl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (78),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(1-methylcyclopropyl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (79),-   (1S,3S)-3-((6-(5-((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic    acid (80),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(1-propylcyclopropyl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (81, 82),-   (1S,3S)-3-((2-Methyl-6-(1-methyl-5-(((methyl(pentan-3-yl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic    acid (83),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(2-methylpentan-2-yl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic    acid (84),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(1-methylcyclopropyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (85),-   (1S,3S)-3-((6-(5-((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic    acid (86),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(1-propylcyclopropyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (87),-   (rac)-trans-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic    acid (88),-   trans-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic    acid (89),-   trans-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic    acid (90),-   trans-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (91),-   cis-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (92),-   cis-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclopentane-1-carboxylic    acid (93),-   (1S,3S)-3-(4-(5-(1-((cyclopentyl(methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylic    acid (94),-   (Cis)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (Enantiomer A, 95),-   (Cis)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (Enantiomer B, 96),-   (1R,3R)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (97),-   (1S,3S)-3-((6-(5-((((2-fluorobenzyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (98),-   (1S,3S)-3-((6-(5-((((1-cyclobutylpropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (99),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(1-phenylcyclopropyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (100),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(3,3,3-trifluoropropyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (101),-   (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (102),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(phenethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (103),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (104),-   (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (105),-   (1S,3S)-3-((6-(5-((((1,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (Enantiomer A, 106)-   (1S,3S)-3-((6-(5-((((1,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (Enantiomer B, 107),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (108),-   (1S,3S)-3-((6-(5-((((cyclopentylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (109),-   (1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-(methyl-d3)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (110),-   (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-(methyl-d3)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (111),-   (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-(methyl-d3)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (112),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-(methyl-d3)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (113),    (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl-d3)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (114),-   (3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic-1-d    acid (115),-   (1S,3S)-3-((6-(5-(((isobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (116),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (117),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyridin-2-ylmethyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (118),-   (1S,3S)-3-((6-(5-(((ethyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (119),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyridin-3-ylmethyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (120),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyrimidin-2-ylmethyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (121),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyridin-4-ylmethyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (122),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyrazin-2-ylmethyl)    carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (123),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (124),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(morpholin-3-ylmethyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (125),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((tetrahydrofuran-3-yl)methyl)    carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (126),-   (1S,3S)-3-((6-(5-(((butyl(ethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (127),-   (1S,3S)-3-((6-(5-(((ethyl(propyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (128),-   (1S,3S)-3-((6-(5-((((1-isopropylcyclopropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (129),-   (1S,3S)-3-((6-(5-((((1-isobutylcyclopropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (130),-   (1S,3S)-3-((6-(5-((((1-ethylcyclopropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (131),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(1-propylcyclobutyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (132),-   (1S,3S)-3-((6-(5-((((1-ethylcyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (133),-   (1S,3S)-3-((6-(5-(((2-azaspiro[3.3]heptane-2-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (134),-   (1S,3S)-3-((6-(5-(((6-azaspiro[3.4]octane-6-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (135),-   (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (136),-   (1S,3S)-3-((6-(5-(((3,3-dimethylpiperidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (137),-   (1S,3S)-3-((6-(5-(((isopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (138),-   (1S,3S)-3-((6-(5-((((3,3-difluorocyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (139),-   (1S,3S)-3-((6-(5-(((3,3-dimethylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (140),-   (1R,3S)-3-((6-(5-((((3,3-difluoro-cyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid; cis isomer from epimerization in    final ester hydrolysis (141),-   (1S,3S)-3-((6-(5-(((cyclopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (142),-   (1S,3S)-3-((6-(5-(((3,3-difluoro-pyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (143),-   (1S,3S)-3-((6-(5-(((5-azaspiro[2.4]heptane-5-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (144),-   (1S,3S)-3-((6-(5-(((((3,3-difluoro-cyclobutyl)methyl)(methyl)carba-moyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (145),-   (1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(spiro[2.3]hexan-1-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (cis isomer from epimerization in final ester hydrolysis)    (146),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-methylpyrrolidine-1-carbonyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (147),-   (1S,3S)-3-((6-(5-(((-2-azabicyclo[2.2.1]heptane-2-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (148),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((octahydrocyclopenta[b]pyrrole-1-carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (149),-   (1S,3S)-3-((6-(5-(((3-(cyclopropylmethyl)pyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (150),-   (1S,3S)-3-((6-(5-(((3-isobutylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (151),-   (1S,3S)-3-((6-(5-(((2-ethylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (152),-   (1S,3S)-3-((6-(5-(((2-isobutylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (153),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((2-(trifluoromethyl)pyrrolidine-1-carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (154),-   (1S,3S)-3-((6-(5-(((3,3-dimethylazetidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (155),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-methylazetidine-1-carbonyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (156),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((2-methylazetidine-1-carbonyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridine-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (157),-   (1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(spiro[3.3]heptan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (158),-   (1S,3S)-3-((6-(5-(((2-azaspiro[3.4]octane-2-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (159),-   (1R,3S)-3-((6-(5-((((3,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (cis isomer from epimerization in final ester hydrolysis step)    (160),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-methylpiperidine-1-carbonyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (161),-   (1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (162),-   (1S,3S)-3-((6-(5-(((3-isopropylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (163),-   (1S,3S)-3-((6-(5-(((3-cyclopropylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (164),-   (1S,3S)-3-((6-(5-(((3-ethylpyrrolidine-1-carbonyl)    oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (165),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-propylpyrrolidine-1-carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (mixture of diastereomers) (166),-   (1S,3S)-3-((6-(5-(((-7-azabicyclo [2.2.1]heptane-7-carbonyl)oxy)    methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (167),-   (1S,3S)-3-((6-(5-((((3,3-dimethyl-cyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (168),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-phenylpyrrolidine-1-carbonyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (169),-   (1S,3S)-3-((6-(5-(((tert-butyl    (methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (170),-   (1S,3S)-3-((6-(5-(((6-azaspiro    [2.5]octane-6-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (171),-   (1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(3-methylbut-2-en-1-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (cis isomer from epimerization during    final hydrolysis step) (172),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (173),-   (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (174),-   (1S,3S)-3-((6-(5-(((6-azaspiro[3.4]octane-6-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (175),-   (1S,3S)-3-((6-(5-(((2-azaspiro[3.3]heptane-2-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (176),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(3-methylbut-2-en-1-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (177),-   (1S,3S)-3-((6-(5-((((1-fluoro-2-methylpropan-2-yl)(methyl)    carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (178),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(spiro[2.3]hexan-5-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (179),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(spiro[3.3]heptan-2-yl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (180),-   (1S,3S)-3-((6-(5-((((3,3-dimethylcyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (181),-   (1S,3S)-3-((6-(5-((((3-fluorocyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (182),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(spiro[2.3]hexan-5-yl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (183),-   (1S,3S)-3-((6-(5-(((((2,2-dimethylcyclopropyl)methyl)(methyl)carbamoyl)oxy)    methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (184),-   (1S,3S)-3-((6-(5-(((((2,2-dimethylcyclopropyl)methyl)(methyl)carbamoyl)oxy)    methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (185),-   (1S,3S)-3-((6-(5-(((((2,2-difluorocyclopropyl)methyl)(methyl)carbamoyl)oxy)    methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (mixture of diastereomers) (186),-   (1S,3S)-3-((6-(5-((((3-fluoro-3-methylbutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (187),-   (1S,3S)-3-((6-(5-((((3-fluoro-3-methylbutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (188),-   (1S,3S)-3-((6-(5-(((((1-fluorocyclobutyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (189),-   (1S,3S)-3-((6-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (190),-   (1S,3S)-3-((6-(5-((((4-fluorobutyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (191),-   (1S,3S)-3-((6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (192),-   (1R,3R)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (193),-   (1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (194),-   (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (195),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (196),-   (1S,3S)-3-((2-ethyl-6-(5-(((isobutyl(methyl)carbamoyl)    oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (197),-   (1S,3S)-3-((6-(5-(((benzylcarbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (198),-   (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (199),-   (1S,3S)-3-((2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (200),-   (1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (201),-   (1S,3S)-3-((2-ethyl-6-(5-(((ethyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (202),-   (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (203),-   (1S,3S)-3-((6-(5-(((3,3-dimethylazetidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (204),-   (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (205),-   (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1-yl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (206),-   (1S,3S)-3-((2-ethyl-6-(1-methyl-5-(((methyl(1-propylcyclopropyl)    carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (207),-   (1S,3S)-3-((2-ethyl-6-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (208),-   (1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (209),-   (1S,3S)-3-((6-(5-(((2-azaspiro[3.3]heptane-2-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (210),-   (1S,3S)-3-((6-(5-(((5-azaspiro[2.4]heptane-5-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (211),-   (1S,3S)-3-((5-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (212),-   (1S,3S)-3-((5-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)    cyclohexane-1-carboxylic acid (213),-   (1S,3S)-3-((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)    cyclohexane-1-carboxylic acid (214),-   (1S,3S)-3-((5-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (215),-   (1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (216),-   (1S,3S)-3-((5-(5-(((butyl    (methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)    cyclohexane-1-carboxylic acid (219),-   (1S,3S)-3-((5-(5-((((cyclopropyl-methyl)(methyl)carbamoyl)    oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methyl-pyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (220),-   (1S,3S)-3-((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (221),-   (1S,3S)-3-((5-(5-(((isopentyl    (methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)    cyclohexane-1-carboxylic acid (222),-   (1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(pentyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (223),-   (1S,3S)-3-((5-(5-(((isobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)    cyclohexane-1-carboxylic acid (224),-   (1S,3S)-3-((5-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)    oxy)cyclohexane-1-carboxylic acid (225),-   (1S,3S)-3-((5-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (226),-   (1S,3S)-3-((5-(5-((((cyclopentylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (227),-   (1S,3S)-3-((5-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)    cyclohexane-1-carboxylic acid (228),-   (1S,3S)-3-((5-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)    oxy)cyclohexane-1-carboxylic acid (229),-   (1S,3S)-3-((5-(5-((((3-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)    oxy)cyclohexane-1-carboxylic acid (230),-   (1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(neopentyl)carbamoyl)    oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (231),-   (1S,3S)-3-((5-(5-((((2-fluoro-2-methylpropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)    oxy)cyclohexane-1-carboxylic acid (232),-   (1S,3S)-3-((5-(5-(((((1-fluoro-cyclobutyl)methyl)(methyl)carbamoyl)oxy)    methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (233),-   (1S,3S)-3-((5-(5-(((((1-fluorocyclopentyl)methyl)(methyl)carbamoyl)oxy)    methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (234),-   (1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(((1R,2R)-2-methylcyclopropyl)    methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (235),-   (1S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(((1S,2S)-2-methyl    cyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid (236),-   (1S,3S)-3-((5-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic    acid (237),-   (1S,3S)-3-((5-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic    acid (238),-   (1S,3S)-3-((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic    acid (239),-   (1S,3S)-3-((5-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic    acid (240),-   (1S,3S)-3-((6-(5-(2-(((Cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (241),-   (1S,3S)-3-((2-Methyl-6-(1-methyl-5-(2-((methyl(propyl)carbamoyl)oxy)-ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid, TFA salt (242),-   (1S,3S)-3-((6-(5-(2-((Cyclopentyl-(methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (243),-   (1S,3S)-3-((6-(5-(2-((Benzyl(methyl)-carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (244),-   (1S,3S)-3-((6-(5-(2-((Isobutyl-(methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (245),-   (1S,3S)-3-((2-Methyl-6-(1-methyl-5-(2-((pyrrolidine-1-carbonyl)oxy)-ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid, TFA salt (246),-   (1S,3S)-3-((6-(5-(2-((Cyclobutyl(methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclo-hexane-1-carboxylic    acid, TFA salt (247),-   (1S,3S)-3-((6-(5-(2-(((Cyclobutyl-methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid, TFA salt (248),-   (1S,3S)-3-((6-(5-(3-((Benzyl(methyl)carbamoyl)oxy)propyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (249),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(2-propoxyethyl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (250),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(((1R,2R)-2-methylcyclopropyl)methyl)    carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (251),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(((1S,2S)-2-methylcyclopropyl)methyl)    carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (252),-   (1S,3S)-3-((6-(5-((((2-fluoro-2-methylpropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (253),-   (1S,3S)-3-((5-(5-((((2-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic    acid; mixture of diastereomers (254),-   (1S,3S)-3-((6-(5-((((2-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid; mixture of diastereomers (255),-   (1S,3S)-3-((6-(5-((((4-fluoropentyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (256),-   (1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1R,2R)-2-methylcyclopropyl)    methyl)    carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (257),-   (1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1S,2S)-2-methylcyclopropyl)    methyl)    carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (258),-   (1S,3S)-3-((6-(5-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (259),-   (1S,3S)-3-((6-(5-((((3-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (260),-   (1S,3S)-3-((6-(5-((((2-fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (261),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((2-methyl    cyclopropyl)methyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)    pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid; mixture of    diastereomers (262),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((1-methylcyclo-propyl)methyl)    carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)    pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (263),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(neopentyl)    carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (264),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (265),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(fluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (266),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (267),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (268),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (269),-   (1S,3S)-3-((2-cyano-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (270),-   (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(2-hydroxypropan-2-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (271),-   (1S,3S)-3-((2-Methoxy-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (272),-   (1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (273),-   (1S,3S)-3-((6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)    oxy)cyclohexane-1-carboxylic acid (274),-   (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (275),-   (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoro    methyl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid (276),-   (1S,3S)-3-((2-(difluoromethyl)-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (277),-   (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (278),-   (1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (279),-   (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)    pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (280),-   (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)    pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (281),-   (1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (282),-   (1S,3S)-3-((2-(methoxymethyl)-6-(1-methyl-5-(((methyl(propyl)    carbamoyl)oxy)    methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (283),-   (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (284),-   (1S,3S)-3-((6-(5-((((cyclopropyl    methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (285),-   (1S,3S)-3-((6-(5-(((cyclobutyl    (methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)    pyridin-3-yl) oxy)cyclohexane-1-carboxylic acid (286),-   (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)    pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (287),-   (1S,3S)-3-((2-methyl-6-(1-methyl-5-((((methyl-d3)(propyl)    carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (288),-   (1S,3S)-3-((2-cyano-6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (289),-   (1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyanopyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (290),-   (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyanopyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (291),-   (1S,3S)-3-((2-cyano-6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (292),-   (1S,3S)-3-((2-cyano-6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic    acid (293),-   (1S,3S)-3-((2-cyano-6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)    cyclohexane-1-carboxylic acid (294).

In another embodiment, the compounds of the present invention have LPA1IC₅₀ values ≤10 μM.

In another embodiment, the compounds of the present invention have LPA1IC₅₀ values ≤1 μM.

In another embodiment, the compounds of the present invention have LPA1IC₅₀ values ≤0.1 μM.

In another embodiment, the compounds of the present invention have LPA1IC₅₀ values ≤0.05 μM.

In another embodiment, the compounds of the present invention have LPA1IC₅₀ values ≤0.01 μM.

II. Other Embodiments of the Invention

In some embodiments, the compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, is an antagonist of at leastone LPA receptor. In some embodiments, the compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof, is anantagonist of LPA₁. In some embodiments, the compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof, is anantagonist of LPA₂. In some embodiments, the compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof, is anantagonist of LPA₃.

In some embodiments, presented herein are compounds selected from activemetabolites, tautomers, pharmaceutically acceptable salts, solvates orprodrugs of a compound of Formulas (I)-(IX).

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s).

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a condition associated with LPA receptormediated fibrosis, comprising administering to a patient in need of suchtreatment and/or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof. Asused herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” is the protective treatment of a diseasestate to reduce and/or minimize the risk and/or reduction in the risk ofrecurrence of a disease state by administering to a patient atherapeutically effective amount of at least one of the compounds of thepresent invention or a or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Patients may be selected forprophylaxis therapy based on factors that are known to increase risk ofsuffering a clinical disease state compared to the general population.For prophylaxis treatment, conditions of the clinical disease state mayor may not be presented yet. “Prophylaxis” treatment can be divided into(a) primary prophylaxis and (b) secondary prophylaxis. Primaryprophylaxis is defined as treatment to reduce or minimize the risk of adisease state in a patient that has not yet presented with a clinicaldisease state, whereas secondary prophylaxis is defined as minimizing orreducing the risk of a recurrence or second occurrence of the same orsimilar clinical disease state.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms.

Alkyl group can be unsubstituted or substituted with at least onehydrogen being replaced by another chemical group. Example alkyl groupsinclude, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g.,n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), andpentyl (e.g., n-pentyl, isopentyl, neopentyl).

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example, methyl-S-and ethyl-S—.

“Halo” or “halogen” includes fluoro (F), chloro (Cl), bromo (Br), andiodo (I). “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogens.Examples of haloalkyl include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl,pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, andheptachloropropyl. Examples of haloalkyl also include “fluoroalkyl” thatis intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more fluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example, trifluoromethyl-S-, andpentafluoroethyl-S-.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₈ cycloalkyl” or “C₃₋₈cycloalkyl” is intended to include C₃, C₄, C₅, C₆, C₇, and C₈ cycloalkylgroups, including monocyclic, bicyclic, and polycyclic rings. Examplecycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkylgroups such as 1-methylcyclopropyl and 2-methylcyclopropyl and spiro andbridged cycloalkyl groups are included in the definition of“cycloalkyl”.

As used herein, “carbocycle”, “carbocyclyl” or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic hydrocarbon ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocyclyl” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocyclyl” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997). “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers tophenyl and naphthyl. Unless otherwise specified, “aryl”, “C₆ or C₁₀aryl” or “C₆₋₁₀ aryl” or “aromatic residue” may be unsubstituted orsubstituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH₃, Cl,F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃,S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicring” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent within thedefinition of the substitution of the heterocyclic ring). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocyclyl” is used, it is intended to includeheteroaryl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group,” “heteroaryl,” or“heteroaryl ring” refers to substituted and unsubstituted aromatic 5- or6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11-to 14-membered tricyclic groups which have at least one heteroatom (0, Sor N) in at least one of the rings, said heteroatom-containing ringpreferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Eachring of the heteroaryl group containing a heteroatom can contain one ortwo oxygen or sulfur atoms and/or from one to four nitrogen atomsprovided that the total number of heteroatoms in each ring is four orless and each ring has at least one carbon atom. Heteroaryl groups canbe substituted or unsubstituted. The nitrogen atom may be substituted orunsubstituted (i.e., N or NR wherein R is H or another substituentwithin the definition of the substitution of the heterocyclic ring). Thenitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N—Oand S(O)_(p)) and the nitrogen atoms may optionally be quaternized.

Heteroaryl groups which are bicyclic or tricyclic must include at leastone fully aromatic ring but the other fused ring or rings may bearomatic or non-aromatic. The heteroaryl group may be attached at anyavailable nitrogen or carbon atom of any ring. The heteroaryl ringsystem may contain zero, one, two or three substituents. Heteroarylgroups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl,benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl,carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, andbenzodioxane.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,PA (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formulas (I)-(IX) may have prodrug forms. Anycompound that will be converted in vivo to provide the bioactive agent(i.e., a compound of formula I) is a prodrug within the scope and spiritof the invention. Various forms of prodrugs are well known in the art.For examples of such prodrug derivatives, see:

-   -   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and        Widder, K. et al., eds., Methods in Enzymology, 112:309-396,        Academic Press (1985);    -   b) Bundgaard, H., Chapter 5, “Design and Application of        Prodrugs”, A Textbook of Drug Design and Development, pp.        113-191, Krosgaard-Larsen, P. et al., eds., Harwood Academic        Publishers (1991);    -   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);    -   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and    -   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formulas (I)-(IX) compounds per se. Such prodrugs arepreferably administered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes.

Parenteral administration may be used where the ester per se is active,or in those instances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formulas (I)-(IX)include C₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well-knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,CA (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for example,when one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

IV. Biology

Lysophospholipids are membrane-derived bioactive lipid mediators.Lysophospholipids include, but are not limited to, lysophosphatidic acid(1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA), sphingosine 1-phosphate(S1P), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine(SPC). Lysophospholipids affect fundamental cellular functions thatinclude cellular proliferation, differentiation, survival, migration,adhesion, invasion, and morphogenesis. These functions influence manybiological processes that include neurogenesis, angiogenesis, woundhealing, immunity, and carcinogenesis.

LPA acts through sets of specific G protein-coupled receptors (GPCRs) inan autocrine and paracrine fashion. LPA binding to its cognate GPCRs(LPA₁, LPA₂, LPA₃, LPA₄, LPA₅, LPA₆) activates intracellular signalingpathways to produce a variety of biological responses.

Lysophospholipids, such as LPA, are quantitatively minor lipid speciescompared to their major phospholipid counterparts (e.g.,phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPAhas a role as a biological effector molecule, and has a diverse range ofphysiological actions such as, but not limited to, effects on bloodpressure, platelet activation, and smooth muscle contraction, and avariety of cellular effects, which include cell growth, cell rounding,neurite retraction, and actin stress fiber formation and cell migration.The effects of LPA are predominantly receptor mediated.

Activation of the LPA receptors (LPA₁, LPA₂, LPA₃, LPA₄, LPA₅, LPA₆)with LPA mediates a range of downstream signaling cascades. Theseinclude, but are not limited to, mitogen-activated protein kinase (MAPK)activation, adenylyl cyclase (AC) inhibition/activation, phospholipase C(PLC) activation/Ca²⁺ mobilization, arachidonic acid release, Akt/PKBactivation, and the activation of small GTPases, Rho, ROCK, Rac, andRas. Other pathways that are affected by LPA receptor activationinclude, but are not limited to, cyclic adenosine monophosphate (cAMP),cell division cycle 42/GTP-binding protein (Cdc42), proto-oncogeneserine/threonine-protein kinase Raf (c-RAF), proto-oncogenetyrosine-protein kinase Src (c-src), extracellular signal-regulatedkinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchangefactor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminalkinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB(NF-kB), N-methyl-D-aspartate (NMDA) receptor activation,phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), proteinkinase C (PKC), ras-related C₃ botulinum toxin substrate 1 (RAC1). Theactual pathway and realized end point are dependent on a range ofvariables that include receptor usage, cell type, expression level of areceptor or signaling protein, and LPA concentration. Nearly allmammalian cells, tissues and organs co-express several LPA-receptorsubtypes, which indicates that LPA receptors signal in a cooperativemanner. LPA₁, LPA₂, and LPA₃ share high amino acid sequence similarity.

LPA is produced from activated platelets, activated adipocytes, neuronalcells, and other cell types. Serum LPA is produced by multiple enzymaticpathways that involve monoacylglycerol kinase, phospholipase A₁,secretory phospholipase A₂, and lysophospholipase D (lysoPLD), includingautotaxin. Several enzymes are involved in LPA degradation:lysophospholipase, lipid phosphate phosphatase, and LPA acyl transferasesuch as endophilin. LPA concentrations in human serum are estimated tobe 1-5 μM. Serum LPA is bound to albumin, low-density lipoproteins, orother proteins, which possibly protect LPA from rapid degradation. LPAmolecular species with different acyl chain lengths and saturation arenaturally occurring, including 1-palmitoyl (16:0), 1-palmitoleoyl(16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and1-arachidonyl (20:4) LPA. Quantitatively minor alkyl LPA has biologicalactivities similar to acyl LPA, and different LPA species activate LPAreceptor subtypes with varied efficacies.

LPA Receptors

LPA1 (previously called VZG-1/EDG-2/mrec1.3) couples with three types ofG proteins, G_(i/o), G_(q), and G_(12/13). Through activation of these Gproteins, LPA induces a range of cellular responses through LPA1including but not limited to: cell proliferation, serum-response element(SRE) activation, mitogen-activated protein kinase (MAPK) activation,adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca²⁺mobilization, Akt activation, and Rho activation.

Wide expression of LPA₁ is observed in adult mice, with clear presencein testis, brain, heart, lung, small intestine, stomach, spleen, thymus,and skeletal muscle. Similarly, human tissues also express LPA₁; it ispresent in brain, heart, lung, placenta, colon, small intestine,prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, andthymus.

LPA₂ (EDG-4) also couples with three types of G proteins, G_(i/o),G_(q), and G_(12/13), to mediate LPA-induced cellular signaling.Expression of LPA₂ is observed in the testis, kidney, lung, thymus,spleen, and stomach of adult mice and in the human testis, pancreas,prostate, thymus, spleen, and peripheral blood leukocytes. Expression ofLPA₂ is upregulated in various cancer cell lines, and several human LPA₂transcriptional variants with mutations in the 3′-untranslated regionhave been observed. Targeted deletion of LPA₂ in mice has not shown anyobvious phenotypic abnormalities, but has demonstrated a significantloss of normal LPA signaling (e.g., PLC activation, Ca²⁺ mobilization,and stress fiber formation) in primary cultures of mouse embryonicfibroblasts (MEFs). Creation of lpa1(−/−) lpa2 (−/−) double-null micehas revealed that many LPA-induced responses, which include cellproliferation, AC inhibition, PLC activation, Ca²⁺ mobilization, JNK andAkt activation, and stress fiber formation, are absent or severelyreduced in double-null MEFs. All these responses, except for ACinhibition (AC inhibition is nearly abolished in LPA₁ (−/−) MEFs), areonly partially affected in either LPA₁ (−/−) or LPA₂ (−/−) MEFs. LPA₂contributes to normal LPA-mediated signaling responses in at least somecell types (Choi et al, Biochemica et Biophysica Acta 2008, 1781, p531-539).

LPA₃ (EDG-7) is distinct from LPA₁ and LPA₂ in its ability to couplewith G_(i/o) and G_(q) but not G_(12/13) and is much less responsive toLPA species with saturated acyl chains. LPA₃ can mediate pleiotropicLPA-induced signaling that includes PLC activation, Ca²⁺ mobilization,AC inhibition/activation, and MAPK activation. Overexpression of LPA₃ inneuroblastoma cells leads to neurite elongation, whereas that of LPA₁ orLPA₂ results in neurite retraction and cell rounding when stimulatedwith LPA. Expression of LPA₃ is observed in adult mouse testis, kidney,lung, small intestine, heart, thymus, and brain. In humans, it is foundin the heart, pancreas, prostate, testis, lung, ovary, and brain(frontal cortex, hippocampus, and amygdala).

LPA₄ (p2y₉/GPR23) is of divergent sequence compared to LPA₁, LPA₂, andLPA₃ with closer similarity to the platelet-activating factor (PAF)receptor. LPA₄ mediates LPA induced Ca²⁺ mobilization and cAMPaccumulation, and functional coupling to the G protein Gs for ACactivation, as well as coupling to other G proteins. The LPA₄ gene isexpressed in the ovary, pancreas, thymus, kidney and skeletal muscle.

LPA_(s)(GPR92) is a member of the purinocluster of GPCRs and isstructurally most closely related to LPA₄. LPA₅ is expressed in humanheart, placenta, spleen, brain, lung and gut. LPA₅ also shows very highexpression in the CD8+lymphocyte compartment of the gastrointestinaltract.

LPA₆ (p2y5) is a member of the purinocluster of GPCRs and isstructurally most closely related to LPA₄. LPA₆ is an LPA receptorcoupled to the G12/13-Rho signaling pathways and is expressed in theinner root sheaths of human hair follicles.

Illustrative Biological Activity

Wound Healing

Normal wound healing occurs by a highly coordinated sequence of eventsin which cellular, soluble factors and matrix components act in concertto repair the injury. The healing response can be described as takingplace in four broad, overlapping phases—hemostasis, inflammation,proliferation, and remodeling. Many growth factors and cytokines arereleased into a wound site to initiate and perpetuate wound healingprocesses.

When wounded, damaged blood vessels activate platelets. The activatedplatelets play pivotal roles in subsequent repair processes by releasingbioactive mediators to induce cell proliferation, cell migration, bloodcoagulation, and angiogenesis. LPA is one such mediator that is releasedfrom activated platelets; this induces platelet aggregation along withmitogenic/migration effects on the surrounding cells, such asendothelial cells, smooth muscle cells, fibroblasts, and keratinocytes.

Topical application of LPA to cutaneous wounds in mice promotes repairprocesses (wound closure and increased neoepithelial thickness) byincreasing cell proliferation/migration without affecting secondaryinflammation.

Activation of dermal fibroblasts by growth factors and cytokines leadsto their subsequent migration from the edges of the wound into theprovisional matrix formed by the fibrin clot whereupon the fibroblastsproliferate and start to restore the dermis by secreting and organizingthe characteristic dermal extracellular matrix (ECM). The increasingnumber of fibroblasts within the wound and continuous precipitation ofECM enhances matrix rigidity by applying small tractional forces to thenewly formed granulation tissue. The increase in mechanical stress, inconjunction with transforming growth factor β (TGFβ), induces α-smoothmuscle actin (α-SMA) expression and the subsequent transformation offibroblasts into myofibroblasts. Myofibroblasts facilitate granulationtissue remodeling via myofibroblast contraction and through theproduction of ECM components.

LPA regulates many important functions of fibroblasts in wound healing,including proliferation, migration, differentiation and contraction.Fibroblast proliferation is required in wound healing in order to fillan open wound. In contrast, fibrosis is characterized by intenseproliferation and accumulation of myofibroblasts that activelysynthesize ECM and proinflammatory cytokines. LPA can either increase orsuppress the proliferation of cell types important in wound healing,such as epithelial and endothelial cells (EC), macrophages,keratinocytes, and fibroblasts. A role for LPA₁ in LPA-inducedproliferation was provided by the observation that LPA-stimulatedproliferation of fibroblasts isolated from LPA₁ receptor null mice wasattenuated (Mills et al, Nat Rev. Cancer 2003; 3: 582-591). LPA inducescytoskeletal changes that are integral to fibroblast adhesion,migration, differentiation and contraction.

Fibrosis

Tissue injury initiates a complex series of host wound-healingresponses; if successful, these responses restore normal tissuestructure and function. If not, these responses can lead to tissuefibrosis and loss of function.

For the majority of organs and tissues the development of fibrosisinvolves a multitude of events and factors. Molecules involved in thedevelopment of fibrosis include proteins or peptides (profibroticcytokines, chemokines, metalloproteinases etc.) and phospholipids.Phospholipids involved in the development of fibrosis include plateletactivating factor (PAF), phosphatidyl choline, sphingosine-1 phosphate(S1P) and lysophosphatidic acid (LPA).

A number of muscular dystrophies are characterized by a progressiveweakness and wasting of musculature, and by extensive fibrosis. It hasbeen shown that LPA treatment of cultured myoblasts induced significantexpression of connective tissue growth factor (CTGF). CTGF subsequentlyinduces collagen, fibronectin and integrin expression and inducesdedifferentiation of these myoblasts. Treatment of a variety of celltypes with LPA induces reproducible and high level induction of CTGF (J.P. Pradere, et al., LPA₁ receptor activation promotes renal interstitialfibrosis, J. Am. Soc. Nephrol. 18 (2007) 3110-3118; N. Wiedmaier, etal., Int J Med Microbiol; 298(3-4):231-43, 2008). CTGF is a profibroticcytokine, signaling down-stream and in parallel with TGFβ.

CTGF expression by gingival epithelial cells, which are involved in thedevelopment of gingival fibromatosis, was found to be exacerbated by LPAtreatment (A. Kantarci, et al., J. Pathol. 210 (2006) 59-66).

LPA is associated with the progression of liver fibrosis. In vitro, LPAinduces stellate cell and hepatocyte proliferation. These activatedcells are the main cell type responsible for the accumulation of ECM inthe liver. Furthermore, LPA plasma levels rise during CCl₄-induced liverfibrosis in rodents, or in hepatitis C virus-induced liver fibrosis inhumans (N. Watanabe, et al., Plasma lysophosphatidic acid level andserum autotaxin activity are increased in liver injury in rats inrelation to its severity, Life Sci. 81 (2007) 1009-1015; N. Watanabe, etal., J. Clin. Gastroenterol. 41 (2007) 616-623).

An increase of phospholipid concentrations in the bronchoalveolar lavagefluid in rabbits and rodents injected with bleomycin has been reported(K. Kuroda, et al., Phospholipid concentration in lung lavage fluid asbiomarker for pulmonary fibrosis, Inhal. Toxicol. 18 (2006) 389-393; K.Yasuda, et al., Lung 172 (1994) 91-102).

LPA is associated with heart disease and mycocardial remodeling. SerumLPA levels are increased after myocardial infarction in patients and LPAstimulates rat cardiac fibroblast proliferation and collagen production(Chen et al. FEBS Lett. 2006 Aug. 21; 580(19):4737-45).

Pulmonary Fibrosis

In the lung, aberrant wound healing responses to injury contribute tothe pathogenesis of fibrotic lung diseases. Fibrotic lung diseases, suchas idiopathic pulmonary fibrosis (IPF), are associated with highmorbidity and mortality.

LPA is an important mediator of fibroblast recruitment in pulmonaryfibrosis. LPA and LPA₁ play key pathogenic roles in pulmonary fibrosis.Fibroblast chemoattractant activity plays an important role in the lungsin patients with pulmonary fibrosis. Profibrotic effects ofLPA₁-receptor stimulation is explained by LPA₁-receptor-mediatedvascular leakage and increased fibroblast recruitment, both profibroticevents. The LPA-LPA₁ pathway has a role in mediating fibroblastmigration and vascular leakage in IPF. The end result is the aberranthealing process that characterizes this fibrotic condition.

The LPA₁ receptor is the LPA receptor most highly expressed onfibroblasts obtained from patients with IPF. Furthermore, BAL obtainedfrom IPF patients induced chemotaxis of human foetal lung fibroblaststhat was blocked by the dual LPA₁-LPA₃ receptor antagonist Ki16425. Inan experimental bleomycin-induced lung injury mouse model, it was shownthat LPA levels were high in bronchoalveolar lavage samples comparedwith unexposed controls. LPA₁ knockout mice are protected from fibrosisafter bleomycin challenge with reduced fibroblast accumulation andvascular leakage. In human subjects with IPF, high LPA levels wereobserved in bronchoalveolar lavage samples compared with healthycontrols. Increased fibroblast chemotactic activity in these samples wasinhibited by the Ki16425 indicating that fibroblast migration ismediated by the LPA-LPA receptor(s) pathway (Tager et al. NatureMedicine, 2008, 14, 45-54).

The LPA-LPA₁ pathway is crucial in fibroblast recruitment and vascularleakage in pulmonary fibrosis.

Activation of latent TGF-β by the αvβ6 integrin plays a critical role inthe development of lung injury and fibrosis (Munger et al. Cell, vol.96, 319-328, 1999). LPA induces αvβ6-mediated TGF-β activation on humanlung epithelial cells (Xu et al. Am. J. Pathology, 2009, 174,1264-1279). The LPA-induced αvβ6-mediated TGF-β activation is mediatedby the LPA₂ receptor. Expression of the LPA₂ receptor is increased inepithelial cells and mesenchymal cells in areas of lung fibrosis fromIPF patients compared to normal human lung tissue. The LPA-LPA₂ pathwaycontributes to the activation of the TGF-β pathway in pulmonaryfibrosis. In some embodiments, compounds that inhibit LPA₂ show efficacyin the treatment of lung fibrosis. In some embodiments, compounds thatinhibit both LPA₁ and LPA₂ show improved efficacy in the treatment oflung fibrosis compared to compounds which inhibit only LPA₁ or LPA₂.

Renal Fibrosis

LPA and LPA₁ are involved in the etiology of kidney fibrosis. LPA haseffects on both proliferation and contraction of glomerular mesangialcells and thus has been implicated in proliferative glomerulonephritis(C. N. Inoue, et al., Clin. Sci. (Colch.) 1999, 96, 431-436). In ananimal model of renal fibrosis [unilateral ureteral obstruction (UUO)],it was found that renal LPA receptors are expressed under basalconditions with an expression order of LPA₂>LPA₃=LPA₁>>LPA₄. This modelmimics in an accelerated manner the development of renal fibrosisincluding renal inflammation, fibroblast activation and accumulation ofextracellular matrix in the tubulointerstitium. UUO significantlyinduced LPA₁-receptor expression. This was paralleled by renal LPAproduction (3.3 fold increase) in conditioned media from kidneyexplants. Contra-lateral kidneys exhibited no significant changes in LPArelease and LPA-receptors expression. This shows that a prerequisite foran action of LPA in fibrosis is met: production of a ligand (LPA) andinduction of one of its receptors (the LPA₁ receptor) (J. P. Pradere etal., Biochimica et Biophysica Acta, 2008, 1781, 582-587).

In mice where the LPA₁ receptor was knocked out (LPA₁ (−/−), thedevelopment of renal fibrosis was significantly attenuated. UUO micetreated with the LPA receptor antagonist Ki16425 closely resembled theprofile of LPA₁ (−/−) mice.

LPA can participate in intraperitonial accumulation ofmonocyte/macrophages and LPA can induce expression of the profibroticcytokine CTGF in primary cultures of human fibroblasts (J. S. Koh, etal., J. Clin. Invest., 1998, 102, 716-727).

LPA treatment of a mouse epithelial renal cell line, MCT, induced arapid increase in the expression of the profibrotic cytokine CTGF. CTGFplays a crucial role in UUO-induced tubulointerstitial fibrosis (TIF),and is involved in the profibrotic activity of TGFβ. This induction wasalmost completely suppressed by co-treatment with the LPA-receptorantagonist Ki16425. In one aspect, the profibrotic activity of LPA inkidney results from a direct action of LPA on kidney cells involvinginduction of CTGF.

Hepatic Fibrosis

LPA is implicated in liver disease and fibrosis. Plasma LPA levels andserum autotaxin (enzyme responsible for LPA production) are elevated inhepatitis patients and animal models of liver injury in correlation withincreased fibrosis. LPA also regulates liver cell function. LPA₁ andLPA₂ receptors are expressed by mouse hepatic stellate cells and LPAstimulates migration of hepatic myofibroblasts.

Ocular Fibrosis

LPA is in involved in wound healing in the eye. LPA₁ and LPA₃ receptorsare detectable in the normal rabbit corneal epithelial cells,keratocytes and endothelial cells and LPA₁ and LPA₃ expression areincreased in corneal epithelial cells following injury.

LPA and its homologues are present in the aqueous humor and the lacrimalgland fluid of the rabbit eye and these levels are increased in a rabbitcorneal injury model.

LPA induces actin stress fiber formation in rabbit corneal endothelialand epithelial cells and promotes contraction corneal fibroblasts. LPAalso stimulates proliferation of human retinal pigmented epithelialcells

Cardiac Fibrosis

LPA is implicated in myocardial infarction and cardiac fibrosis. SerumLPA levels are increased in patients following mycocardial infarction(MI) and LPA stimulates proliferation and collagen production (fibrosis)by rat cardiac fibroblasts. Both LPA₁ and LPA₃ receptors are highlyexpressed in human heart tissue.

Treatment of Fibrosis

In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used to treat or prevent fibrosis in amammal. In one aspect, a compound of Formulas (I-(IX)), or apharmaceutically acceptable salt thereof, is used to treat fibrosis ofan organ or tissue in a mammal. In one aspect is a method for preventinga fibrosis condition in a mammal, the method comprising administering tothe mammal at risk of developing one or more fibrosis conditions atherapeutically effective amount of a compound of Formulas (I-(IX)), ora pharmaceutically acceptable salt thereof. In one aspect, the mammalhas been exposed to one or more environmental conditions that are knownto increase the risk of fibrosis of an organ or tissue. In one aspect,the mammal has been exposed to one or more environmental conditions thatare known to increase the risk of lung, liver or kidney fibrosis. In oneaspect, the mammal has a genetic predisposition of developing fibrosisof an organ or tissue. In one aspect, a compound of Formulas (I)-(IX),or a pharmaceutically acceptable salt thereof, is administered to amammal to prevent or minimize scarring following injury. In one aspect,injury includes surgery.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers toconditions that are associated with the abnormal accumulation of cellsand/or fibronectin and/or collagen and/or increased fibroblastrecruitment and include but are not limited to fibrosis of individualorgans or tissues such as the heart, kidney, liver, joints, lung,pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletaland digestive tract.

Exemplary diseases, disorders, or conditions that involve fibrosisinclude, but are not limited to: Lung diseases associated with fibrosis,e.g., idiopathic pulmonary fibrosis, pulmonary fibrosis secondary tosystemic inflammatory disease such as rheumatoid arthritis, scleroderma,lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis,chronic obstructive pulmonary disease (COPD), scleroderma, chronicasthma, silicosis, asbestos induced pulmonary or pleural fibrosis, acutelung injury and acute respiratory distress (including bacterialpneumonia induced, trauma induced, viral pneumonia induced, ventilatorinduced, non-pulmonary sepsis induced, and aspiration induced); Chronicnephropathies associated with injury/fibrosis (kidney fibrosis), e.g.,glomerulonephritis secondary to systemic inflammatory diseases such aslupus and scleroderma, diabetes, glomerular nephritis, focal segmentalglomerular sclerosis, IgA nephropathy, hypertension, allograft andAlport; Gut fibrosis, e.g., scleroderma, and radiation induced gutfibrosis; Liver fibrosis, e.g., cirrhosis, alcohol induced liverfibrosis, nonalcoholic steatohepatitis (NASH), biliary duct injury,primary biliary cirrhosis, infection or viral induced liver fibrosis(e.g., chronic HCV infection), and autoimmune hepatitis; Head and neckfibrosis, e.g., radiation induced; Corneal scarring, e.g., LASIK(laser-assisted in situ keratomileusis), corneal transplant, andtrabeculectomy; Hypertrophic scarring and keloids, e.g., burn induced orsurgical; and other fibrotic diseases, e.g., sarcoidosis, scleroderma,spinal cord injury/fibrosis, myelofibrosis, vascular restenosis,atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixedconnective tissue disease, and Peyronie's disease.

In one aspect, a mammal suffering from one of the following non-limitingexemplary diseases, disorders, or conditions will benefit from therapywith a compound of Formulas (I)-(IX), or a pharmaceutically acceptablesalt thereof: atherosclerosis, thrombosis, heart disease, vasculitis,formation of scar tissue, restenosis, phlebitis, COPD (chronicobstructive pulmonary disease), pulmonary hypertension, pulmonaryfibrosis, pulmonary inflammation, bowel adhesions, bladder fibrosis andcystitis, fibrosis of the nasal passages, sinusitis, inflammationmediated by neutrophils, and fibrosis mediated by fibroblasts.

In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is administered to a mammal with fibrosis of anorgan or tissue or with a predisposition of developing fibrosis of anorgan or tissue with one or more other agents that are used to treatfibrosis. In one aspect, the one or more agents include corticosteroids.In one aspect, the one or more agents include immunosuppressants. In oneaspect, the one or more agents include B-cell antagonists. In oneaspect, the one or more agents include uteroglobin.

In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used to treat a dermatological disorders ina mammal. The term “dermatological disorder,” as used herein refers to askin disorder. Such dermatological disorders include, but are notlimited to, proliferative or inflammatory disorders of the skin such as,atopic dermatitis, bullous disorders, collagenoses, psoriasis,scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema,urticaria, rosacea, wound healing, scarring, hypertrophic scarring,keloids, Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria.In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used to treat systemic sclerosis.

Pain

Since LPA is released following tissue injury, LPA₁ plays an importantrole in the initiation of neuropathic pain. LPA₁, unlike LPA₂ or LPA₃,is expressed in both dorsal root ganglion (DRG) and dorsal root neurons.Using the antisense oligodeoxynucleotide (AS-ODN) for LPA₁ and LPA₁-nullmice, it was found that LPA-induced mechanical allodynia andhyperalgesia is mediated in an LPA₁-dependent manner. LPA₁ anddownstream Rho-ROCK activation play a role in the initiation ofneuropathic pain signaling. Pretreatment with Clostridium botulinum C₃exoenzyme (BoTXC3, Rho inhibitor) or Y-27632 (ROCK inhibitor) completelyabolished the allodynia and hyperalgesia in nerve-injured mice. LPA alsoinduced demyelination of the dorsal root, which was prevented by BoTXC3.The dorsal root demyelination by injury was not observed in LPA₁-nullmice or AS-ODN injected wild-type mice. LPA signaling appears to induceimportant neuropathic pain markers such as protein kinase Cγ (PKCγ) anda voltage-gated calcium channel α2δ1 subunit (Caα2δ1) in an LPA₁ andRho-dependent manner (M. Inoue, et al., Initiation of neuropathic painrequires lysophosphatidic acid receptor signaling, Nat. Med. 10 (2004)712-718).

In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used in the treatment of pain in a mammal.In one aspect, the pain is acute pain or chronic pain. In anotheraspect, the pain is neuropathic pain.

In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used in the treatment of fibromylagia. Inone aspect, fibromyalgia stems from the formation of fibrous scar tissuein contractile (voluntary) muscles. Fibrosis binds the tissue andinhibits blood flow, resulting in pain.

Cancer

Lysophospholipid receptor signaling plays a role in the etiology ofcancer. Lysophosphatidic acid (LPA) and its G protein-coupled receptors(GPCRs) LPA₁, LPA₂, and/or LPA₃ play a role in the development ofseveral types of cancers. The initiation, progression and metastasis ofcancer involve several concurrent and sequential processes includingcell proliferation and growth, survival and anti-apoptosis, migration ofcells, penetration of foreign cells into defined cellular layers and/ororgans, and promotion of angiogenesis. The control of each of theseprocesses by LPA signaling in physiological and pathophysiologicalconditions underscores the potential therapeutic usefulness ofmodulating LPA signaling pathways for the treatment of cancer,especially at the level of the LPA receptors or ATX/lysoPLD. Autotaxin(ATX) is a prometastatic enzyme initially isolated from the conditionedmedium of human melanoma cells that stimulates a myriad of biologicalactivities, including angiogenesis and the promotion of cell growth,migration, survival, and differentiation through the production of LPA(Mol Cancer Ther 2008; 7(10):3352-62).

LPA signals through its own GPCRs leading to activation of multipledownstream effector pathways. Such downstream effector pathways play arole in cancer. LPA and its GPCRs are linked to cancer through majoroncogenic signaling pathways.

LPA contributes to tumorigenesis by increasing motility and invasivenessof cells. LPA has been implicated in the initiation or progression ofovarian cancer. LPA is present at significant concentrations (2-80 μM)in the ascitic fluid of ovarian cancer patients. Ovarian cancer cellsconstitutively produce increased amounts of LPA as compared to normalovarian surface epithelial cells, the precursor of ovarian epithelialcancer. Elevated LPA levels are also detected in plasma from patientswith early-stage ovarian cancers compared with controls. LPA receptors(LPA2 and LPA3) are also overexpressed in ovarian cancer cells ascompared to normal ovarian surface epithelial cells. LPA stimulatesCox-2 expression through transcriptional activation andpost-transcriptional enhancement of Cox-2 mRNA in ovarian cancer cells.Prostaglandins produced by Cox-2 have been implicated in a number ofhuman cancers and pharmacological inhibition of Cox-2 activity reducescolon cancer development and decreases the size and number of adenomasin patients with familial adenomatous polyposis. LPA has also beenimplicated in the initiation or progression of prostate cancer, breastcancer, melanoma, head and neck cancer, bowel cancer (colorectalcancer), thyroid cancer and other cancers (Gardell et al, Trends inMolecular Medicine, vol. 12, no. 2, p 65-75, 2006; Ishii et al, Annu.Rev. Biochem, 73, 321-354, 2004; Mills et al., Nat. Rev. Cancer, 3,582-591, 2003; Murph et al., Biochimica et Biophysica Acta, 1781,547-557, 2008).

The cellular responses to LPA are mediated through the lysophosphatidicacid receptors. For example, LPA receptors mediate both migration of andinvasion by pancreatic cancer cell lines: an antagonist of LPA₁ and LPA₃(Ki16425) and LPA₁-specific siRNA effectively blocked in vitro migrationin response to LPA and peritoneal fluid (ascites) from pancreatic cancerpatients; in addition, Ki16425 blocked the LPA-induced andascites-induced invasion activity of a highly peritoneal metastaticpancreatic cancer cell line (Yamada et al, J. Biol. Chem., 279,6595-6605, 2004).

Colorectal carcinoma cell lines show significant expression of LPA₁ mRNAand respond to LPA by cell migration and production of angiogenicfactors. Overexpression of LPA receptors has a role in the pathogenesisof thyroid cancer. LPA₃ was originally cloned from prostate cancercells, concordant with the ability of LPA to induce autocrineproliferation of prostate cancer cells.

LPA has stimulatory roles in cancer progression in many types of cancer.LPA is produced from and induces proliferation of prostate cancer celllines. LPA induces human colon carcinoma DLD1 cell proliferation,migration, adhesion, and secretion of angiogenic factors through LPA₁signaling. In other human colon carcinoma cells lines (HT29 and WiDR),LPA enhances cell proliferation and secretion of angiogenic factors. Inother colon cancer cell lines, LPA₂ and LPA₃ receptor activation resultsin proliferation of the cells. The genetic or pharmacologicalmanipulation of LPA metabolism, specific blockade of receptor signaling,and/or inhibition of downstream signal transduction pathways, representapproaches for cancer therapies.

It has been reported that LPA and other phospholipids stimulateexpression of interleukin-8 (IL-8) in ovarian cancer cell lines. In someembodiments, high concentrations of IL-8 in ovarian cancer correlatewith poor initial response to chemotherapy and with poor prognosis,respectively. In animal models, expression of IL-8 and other growthfactors such as vascular endothelial growth factor (VEGF) is associatedwith increased tumorigenicity, ascites formation, angiogenesis, andinvasiveness of ovarian cancer cells. In some aspects, IL-8 is animportant modulator of cancer progression, drug resistance, andprognosis in ovarian cancer. In some embodiments, a compound of Formulas(I)-(IX) inhibits or reduces IL-8 expression in ovarian cancer celllines.

In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used in the treatment of cancer. In oneaspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used in the treatment of malignant andbenign proliferative disease. In one aspect, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is used to prevent orreduce proliferation of tumor cells, invasion and metastasis ofcarcinomas, pleural mesothelioma (Yamada, Cancer Sci., 2008, 99(8),1603-1610) or peritoneal mesothelioma, cancer pain, bone metastases(Boucharaba et al, J. Clin. Invest., 2004, 114(12), 1714-1725;Boucharaba et al, Proc. Natd. acad. Sci., 2006, 103(25) 9643-9648). Inone aspect is a method of treating cancer in a mammal, the methodcomprising administering to the mammal a compound of Formulas (I)-(IX),or a pharmaceutically acceptable salt thereof, and a second therapeuticagent, wherein the second therapeutic agent is an anti-cancer agent.

The term “cancer,” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma orbasal cell cancer) or hematological tumors (such as the leukemias) atany stage of the disease with or without metastases.

Additional non-limiting examples of cancers include, acute lymphoblasticleukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer,appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer(osteosarcoma and malignant fibrous histiocytoma), brain stem glioma,brain tumors, brain and spinal cord tumors, breast cancer, bronchialtumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia,chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-Cell lymphoma, embryonal tumors,endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer,ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladdercancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), gastrointestinal stromal celltumor, germ cell tumor, glioma, hairy cell leukemia, head and neckcancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngealcancer, intraocular melanoma, islet cell tumors (endocrine pancreas),Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngealcancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, liver cancer, non-small cell lung cancer, small cell lungcancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma,non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia,medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouthcancer, chronic myelogenous leukemia, myeloid leukemia, multiplemyeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,non-small cell lung cancer, oral cancer, oropharyngeal cancer,osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, papillomatosis,parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymaltumors of intermediate differentiation, pineoblastoma and supratentorialprimitive neuroectodermal tumors, pituitary tumor, plasma cellneoplasm/multiple myeloma, pleuropulmonary blastoma, primary centralnervous system lymphoma, prostate cancer, rectal cancer, renal cell(kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sézarysyndrome, skin cancer, small cell Lung cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, T-cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor.

The increased concentrations of LPA and vesicles in ascites from ovariancancer patients and breast cancer effussions indicate that it could bean early diagnostic marker, a prognostic indicator or an indicator ofresponse to therapy (Mills et al, Nat. Rev. Cancer., 3, 582-591, 2003;Sutphen et al., Cancer Epidemiol. Biomarkers Prev. 13, 1185-1191, 2004).LPA concentrations are consistently higher in ascites samples than inmatched plasma samples.

Respiratory and Allergic Disorders

In one aspect, LPA is a contributor to the pathogenesis of respiratorydiseases. In one aspect the respiratory disease is asthma.Proinflammatory effects of LPA include degranulation of mast cells,contraction of smooth-muscle cells and release of cytokines fromdendritic cells. Airway smooth muscle cells, epithelial cells and lungfibroblasts all show responses to LPA. LPA induces the secretion of IL-8from human bronchial epithelial cells. IL-8 is found in increasedconcentrations in BAL fluids from patients with asthma, chronicobstructive lung disease, pulmonary sarcoidosis and acute respiratorydistress syndrome and 11-8 has been shown to exacerbate airwayinflammation and airway remodeling of asthmatics. LPA1, LPA2 and LPA3receptors have all been shown to contribute to the LPA-induced IL-8production. Studies cloning multiple GPCRs that are activated by LPAallowed the demonstration of the presence of mRNA for the LPA₁, LPA₂ andLPA₃ in the lung (J. J. A. Contos, et al., Mol. Pharmacol. 58,1188-1196, 2000).

The release of LPA from platelets activated at a site of injury and itsability to promote fibroblast proliferation and contraction are featuresof LPA as a mediator of wound repair. In the context of airway disease,asthma is an inflammatory disease where inappropriate airway “repair”processes lead to structural “remodeling” of the airway. In asthma, thecells of the airway are subject to ongoing injury due to a variety ofinsults, including allergens, pollutants, other inhaled environmentalagents, bacteria and viruses, leading to the chronic inflammation thatcharacterizes asthma.

In one aspect, in the asthmatic individual, the release of normal repairmediators, including LPA, is exaggerated or the actions of the repairmediators are inappropriately prolonged leading to inappropriate airwayremodeling. Major structural features of the remodeled airway observedin asthma include a thickened lamina reticularis (the basementmembrane-like structure just beneath the airway epithelial cells),increased numbers and activation of myofibroblasts, thickening of thesmooth muscle layer, increased numbers of mucus glands and mucussecretions, and alterations in the connective tissue and capillary bedthroughout the airway wall. In one aspect, LPA contributes to thesestructural changes in the airway. In one aspect, LPA is involved inacute airway hyperresponsiveness in asthma. The lumen of the remodeledasthmatic airway is narrower due to the thickening of the airway wall,thus decreasing airflow. In one aspect, LPA contributes to the long-termstructural remodeling and the acute hyperresponsiveness of the asthmaticairway. In one aspect, LPA contributes to the hyper-responsiveness thatis a primary feature of acute exacerbations of asthma.

In addition to the cellular responses mediated by LPA, several of theLPA signaling pathway components leading to these responses are relevantto asthma. EGF receptor upregulation is induced by LPA and is also seenin asthmatic airways (M. Amishima, et al., Am. J. Respir. Crit. CareMed. 157, 1907-1912, 1998). Chronic inflammation is a contributor toasthma, and several of the transcription factors that are activated byLPA are known to be involved in inflammation (Ediger et al., Eur RespirJ 21:759-769, 2003).

In one aspect, the fibroblast proliferation and contraction andextracellular matrix secretion stimulated by LPA contributes to thefibroproliferative features of other airway diseases, such as theperibronchiolar fibrosis present in chronic bronchitis, emphysema, andinterstitial lung disease. Emphysema is also associated with a mildfibrosis of the alveolar wall, a feature which is believed to representan attempt to repair alveolar damage. In another aspect, LPA plays arole in the fibrotic interstitial lung diseases and obliterativebronchiolitis, where both collagen and myofibroblasts are increased. Inanother aspect, LPA is involved in several of the various syndromes thatconstitute chronic obstructive pulmonary disease.

Administration of LPA in vivo induces airway hyper-responsiveness,itch-scratch responses, infiltration and activation of eosinophils andneutrophils, vascular remodeling, and nociceptive flexor responses. LPAalso induces histamine release from mouse and rat mast cells. In anacute allergic reaction, histamine induces various responses, such ascontraction of smooth muscle, plasma exudation, and mucus production.Plasma exudation is important in the airway, because the leakage andsubsequent airway-wall edema contribute to the development of airwayhyperresponsiveness. Plasma exudation progresses to conjunctivalswelling in ocular allergic disorder and nasal blockage in allergicrhinitis (Hashimoto et al., J Pharmacol Sci 100, 82-87, 2006). In oneaspect, plasma exudation induced by LPA is mediated by histamine releasefrom mast cells via one or more LPA receptors. In one aspect, the LPAreceptor(s) include LPA₁ and/or LPA₃. In one aspect, a compound ofFormulas (I)-(IX), or a pharmaceutically acceptable salt thereof, isused in the treatment of various allergic disorders in a mammal. In oneaspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used in the treatment of respiratorydiseases, disorders or conditions in a mammal. In one aspect, a compoundof Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof, isused in the treatment of asthma in a mammal. In one aspect, a compoundof Formulas (I)-(IX), or a pharmaceutically acceptable salt thereof, isused in the treatment of chronic asthma in a mammal.

The term “respiratory disease,” as used herein, refers to diseasesaffecting the organs that are involved in breathing, such as the nose,throat, larynx, eustachian tubes, trachea, bronchi, lungs, relatedmuscles (e.g., diaphram and intercostals), and nerves. Respiratorydiseases include, but are not limited to, asthma, adult respiratorydistress syndrome and allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, isocapnic hyperventilation, child-onsetasthma, adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis,perennial allergic rhinitis, chronic obstructive pulmonary disease,including chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis, and hypoxia.

The term “asthma” as used herein refers to any disorder of the lungscharacterized by variations in pulmonary gas flow associated with airwayconstriction of whatever cause (intrinsic, extrinsic, or both; allergicor non-allergic). The term asthma may be used with one or moreadjectives to indicate cause.

In one aspect, presented herein is the use of a compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof, in thetreatment or prevention of chronic obstructive pulmonary disease in amammal comprising administering to the mammal at least once an effectiveamount of at least one compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof. In addition, chronicobstructive pulmonary disease includes, but is not limited to, chronicbronchitis or emphysema, pulmonary hypertension, interstitial lungfibrosis and/or airway inflammation, and cystic fibrosis.

Nervous System

The nervous system is a major locus for LPA₁ expression; there it isspatially and temporally regulated throughout brain development.Oligodendrocytes, the myelinating cells in the central nervous system(CNS), express LPA₁ in mammals. In addition, Schwann cells, themyelinating cells of the peripheral nervous system, also express LPA₁,which is involved in regulating Schwann cell survival and morphology.These observations identify important functions for receptor-mediatedLPA signaling in neurogenesis, cell survival, and myelination.

Exposure of peripheral nervous system cell lines to LPA produces a rapidretraction of their processes resulting in cell rounding, which was, inpart, mediated by polymerization of the actin cytoskeleton. In oneaspect, LPA causes neuronal degeneration under pathological conditionswhen the blood-brain barrier is damaged and serum components leak intothe brain (Moolenaar, Curr. Opin. Cell Biol. 7:203-10, 1995).Immortalized CNS neuroblast cell lines from the cerebral cortex alsodisplay retraction responses to LPA exposure through Rho activation andactomyosin interactions. In one aspect, LPA is associated withpost-ischemic neural damage (J. Neurochem. 61, 340, 1993; J. Neurochem.,70:66, 1998).

In one aspect, provided is a compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, for use in the treatment orprevention of a nervous system disorder in a mammal. The term “nervoussystem disorder,” as used herein, refers to conditions that alter thestructure or function of the brain, spinal cord or peripheral nervoussystem, including but not limited to Alzheimer's Disease, cerebraledema, cerebral ischemia, stroke, multiple sclerosis, neuropathies,Parkinson's Disease, those found after blunt or surgical trauma(including post-surgical cognitive dysfunction and spinal cord or brainstem injury), as well as the neurological aspects of disorders such asdegenerative disk disease and sciatica.

In one aspect, provided is a compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, for use in the treatment orprevention of a CNS disorder in a mammal. CNS disorders include, but arenot limited to, multiple sclerosis, Parkinson's disease, Alzheimer'sdisease, stroke, cerebral ischemia, retinal ischemia, post-surgicalcognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain,spinal cord injury, cerebral edema and head injury.

Cardiovascular Disorders

Cardiovascular phenotypes observed after targeted deletion oflysophospholipid receptors reveal important roles for lysophospholipidsignaling in the development and maturation of blood vessels, formationof atherosclerotic plaques and maintenance of heart rate (Ishii, I. etal. Annu. Rev. Biochem. 73, 321-354, 2004). Angiogenesis, the formationof new capillary networks from pre-existing vasculature, is normallyinvoked in wound healing, tissue growth and myocardial angiogenesisafter ischemic injury. Peptide growth factors (e.g. vascular endothelialgrowth factor (VEGF)) and lysophospholipids control coordinatedproliferation, migration, adhesion, differentiation and assembly ofvascular endothelial cells (VECs) and surrounding vascular smooth-musclecells (VSMCs). In one aspect, dysregulation of the processes mediatingangiogenesis leads to atherosclerosis, hypertension, tumor growth,rheumatoid arthritis and diabetic retinopathy (Osborne, N. and Stainier,D. Y. Annu. Rev. Physiol. 65, 23-43, 2003).

Downstream signaling pathways evoked by lysophospholipid receptorsinclude Rac-dependent lamellipodia formation (e.g. LPA₁) andRho-dependent stress-fiber formation (e.g. LPA₁), which is important incell migration and adhesion. Dysfunction of the vascular endothelium canshift the balance from vasodilatation to vasoconstriction and lead tohypertension and vascular remodeling, which are risk factors foratherosclerosis (Maguire, J. J. et al., Trends Pharmacol. Sci. 26,448-454, 2005).

LPA contributes to both the early phase (barrier dysfunction andmonocyte adhesion of the endothelium) and the late phase (plateletactivation and intra-arterial thrombus formation) of atherosclerosis, inaddition to its overall progression. In the early phase, LPA fromnumerous sources accumulates in lesions and activates its cognate GPCRs(LPA₁ and LPA₃) expressed on platelets (Siess, W. Biochim. Biophys. Acta1582, 204-215, 2002; Rother, E. et al. Circulation 108, 741-747, 2003).This triggers platelet shape change and aggregation, leading tointra-arterial thrombus formation and, potentially, myocardialinfarction and stroke. In support of its atherogenic activity, LPA canalso be a mitogen and motogen to VSMCs and an activator of endothelialcells and macrophages. In one aspect, mammals with cardiovasculardisease benefit from LPA receptor antagonists that prevent thrombus andneointima plaque formation.

In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used to treat or prevent cardiovasculardisease in mammal.

The term “cardiovascular disease,” as used herein refers to diseasesaffecting the heart or blood vessels or both, including but not limitedto: arrhythmia (atrial or ventricular or both); atherosclerosis and itssequelae; angina; cardiac rhythm disturbances; myocardial ischemia;myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke;peripheral obstructive arteriopathy of a limb, an organ, or a tissue;reperfusion injury following ischemia of the brain, heart or other organor tissue; endotoxic, surgical, or traumatic shock; hypertension,valvular heart disease, heart failure, abnormal blood pressure; shock;vasoconstriction (including that associated with migraines); vascularabnormality, inflammation, insufficiency limited to a single organ ortissue.

In one aspect, provided herein are methods for preventing or treatingvasoconstriction, atherosclerosis and its sequelae myocardial ischemia,myocardial infarction, aortic aneurysm, vasculitis and stroke comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, or pharmaceutical composition or medicamentwhich includes a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof.

In one aspect, provided herein are methods for reducing cardiacreperfusion injury following myocardial ischemia and/or endotoxic shockcomprising administering at least once to the mammal an effective amountof at least one compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof.

In one aspect, provided herein are methods for reducing the constrictionof blood vessels in a mammal comprising administering at least once tothe mammal an effective amount of at least one compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are methods for lowering or preventing anincrease in blood pressure of a mammal comprising administering at leastonce to the mammal an effective amount of at least one compound ofFormulas (I)-(IX), or a pharmaceutically acceptable salt thereof.

Inflammation

LPA has been shown to regulate immunological responses by modulatingactivities/functions of immune cells such as T-/B-lymphocytes andmacrophages. In activated T cells, LPA activates IL-2 production/cellproliferation through LPA₁ (Gardell et al, TRENDS in Molecular MedicineVol. 12 No. 2 Feb. 2006). Expression of LPA-induced inflammatoryresponse genes is mediated by LPA₁ and LPA₃ (Biochem Biophys Res Commun.363(4):1001-8, 2007). In addition, LPA modulates the chemotaxis ofinflammatory cells (Biochem Biophys Res Commun., 1993, 15; 193(2), 497).The proliferation and cytokine-secreting activity in response to LPA ofimmune cells (J. Imuunol. 1999, 162, 2049), platelet aggregationactivity in response to LPA, acceleration of migration activity inmonocytes, activation of NF-κB in fibroblast, enhancement offibronectin-binding to the cell surface, and the like are known. Thus,LPA is associated with various inflammatory/immune diseases.

In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used to treat or prevent inflammation in amammal. In one aspect, antagonists of LPA₁ and/or LPA₃ find use in thetreatment or prevention of inflammatory/immune disorders in a mammal. Inone aspect, the antagonist of LPA₁ is a compound of Formulas (I)-(IX),or a pharmaceutically acceptable salt thereof.

Examples of inflammatory/immune disorders include psoriasis, rheumatoidarthritis, vasculitis, inflammatory bowel disease, dermatitis,osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis,vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic orxenogeneic transplantation (organ, bone marrow, stem cells and othercells and tissues) graft rejection, graft-versus-host disease, lupuserythematosus, inflammatory disease, type I diabetes, pulmonaryfibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g.,Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmunehemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsinghepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopicdermatitis.

Other Diseases, Disorders or Conditions

In accordance with one aspect, are methods for treating, preventing,reversing, halting or slowing the progression of LPA-dependent orLPA-mediated diseases or conditions once it becomes clinically evident,or treating the symptoms associated with or related to LPA-dependent orLPA-mediated diseases or conditions, by administering to the mammal acompound of Formulas (I)-(IX), or a pharmaceutically acceptable saltthereof. In certain embodiments, the subject already has a LPA-dependentor LPA-mediated disease or condition at the time of administration, oris at risk of developing a LPA-dependent or LPA-mediated disease orcondition.

In certain aspects, the activity of LPA₁ in a mammal is directly orindirectly modulated by the administration of (at least once) atherapeutically effective amount of at least one compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof. Such modulationincludes, but is not limited to, reducing and/or inhibiting the activityof LPA₁. In additional aspects, the activity of LPA in a mammal isdirectly or indirectly modulated, including reducing and/or inhibiting,by the administration of (at least once) a therapeutically effectiveamount of at least one compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof. Such modulation includes, butis not limited to, reducing and/or inhibiting the amount and/or activityof a LPA receptor. In one aspect, the LPA receptor is LPA₁.

In one aspect, LPA has a contracting action on bladder smooth musclecell isolated from bladder, and promotes growth of prostate-derivedepithelial cell (J. Urology, 1999, 162, 1779-1784; J. Urology, 2000,163, 1027-1032). In another aspect, LPA contracts the urinary tract andprostate in vitro and increases intraurethral pressure in vivo (WO02/062389).

In certain aspects, are methods for preventing or treating eosinophiland/or basophil and/or dendritic cell and/or neutrophil and/or monocyteand/or T-cell recruitment comprising administering at least once to themammal an effective amount of at least one compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof.

In certain aspects, are methods for the treatment of cystitis,including, e.g., interstitial cystitis, comprising administering atleast once to the mammal a therapeutically effective amount of at leastone compound of Formulas (I)-(IX), or a pharmaceutically acceptable saltthereof.

In accordance with one aspect, methods described herein include thediagnosis or determination of whether or not a patient is suffering froma LPA-dependent or LPA-mediated disease or condition by administering tothe subject a therapeutically effective amount of a compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof, and determiningwhether or not the patient responds to the treatment.

In one aspect provided herein are compounds of Formulas (I)-(IX),pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs,and pharmaceutically acceptable solvates thereof, which are antagonistsof LPA₁, and are used to treat patients suffering from one or moreLPA-dependent or LPA-mediated conditions or diseases, including, but notlimited to, lung fibrosis, kidney fibrosis, liver fibrosis, scarring,asthma, rhinitis, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis,inflammatory bowel disease, adult respiratory distress syndrome,myocardial infarction, aneurysm, stroke, cancer, pain, proliferativedisorders and inflammatory conditions. In some embodiments,LPA-dependent conditions or diseases include those wherein an absoluteor relative excess of LPA is present and/or observed.

In any of the aforementioned aspects the LPA-dependent or LPA-mediateddiseases or conditions include, but are not limited to, organ fibrosis,asthma, allergic disorders, chronic obstructive pulmonary disease,pulmonary hypertension, lung or pleural fibrosis, peritoneal fibrosis,arthritis, allergy, cancer, cardiovascular disease, ult respiratorydistress syndrome, myocardial infarction, aneurysm, stroke, and cancer.

In one aspect, a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, is used to improve the corneal sensitivitydecrease caused by corneal operations such as laser-assisted in situkeratomileusis (LASIK) or cataract operation, corneal sensitivitydecrease caused by corneal degeneration, and dry eye symptom causedthereby.

In one aspect, presented herein is the use of a compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof, in thetreatment or prevention of ocular inflammation and allergicconjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis in a mammal comprising administering at least once to themammal an effective amount of at least one compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof.

In one aspect, presented herein is the use of a compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof, in thetreatment or prevention of Sjogren disease or inflammatory disease withdry eyes in a mammal comprising administering at least once to themammal an effective amount of at least one compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof.

In one aspect, LPA and LPA receptors (e.g. LPA₁) are involved in thepathogenesis of osteoarthritis (Kotani et al, Hum. Mol. Genet., 2008,17, 1790-1797). In one aspect, presented herein is the use of a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, in thetreatment or prevention of osteoarthritis in a mammal comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof.

In one aspect, LPA receptors (e.g. LPA₁, LPA₃) contribute to thepathogenesis of rheumatoid arthritis (Zhao et al, Mol. Pharmacol., 2008,73(2), 587-600). In one aspect, presented herein is the use of acompound of Formulas (I)-(IX), or a pharmaceutically acceptable saltthereof, in the treatment or prevention of rheumatoid arthritis in amammal comprising administering at least once to the mammal an effectiveamount of at least one compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof.

In one aspect, LPA receptors (e.g. LPA₁) contribute to adipogenesis.(Simon et al, J. Biol. Chem., 2005, vol. 280, no. 15, p. 14656). In oneaspect, presented herein is the use of a compound of Formulas (I)-(IX),or a pharmaceutically acceptable salt thereof, in the promotion ofadipose tissue formation in a mammal comprising administering at leastonce to the mammal an effective amount of at least one compound ofFormulas (I)-(IX), or a pharmaceutically acceptable salt thereof.

a. In Vitro Assays

The effectiveness of compounds of the present invention as LPA1inhibitors can be determined in an LPA1 functional antagonist assay asfollows: Chinese hamster ovary cells overexpressing human LPA1 wereplated overnight (15,000 cells/well) in poly-D-lysine coated 384-wellmicroplates (Greiner bio-one, Cat #781946) in DMEM/F12 medium (Gibco,Cat #11039). Following overnight culture, cells were loaded with calciumindicator dye (AAT Bioquest Inc, Cat #34601) for 30 minutes at 37° C.The cells were then equilibrated to room temperature for 30 minutesbefore the assay. Test compounds solubilized in DMSO were transferred to384 well non-binding surface plates (Corning, Cat #3575) using theLabcyte Echo acoustic dispense and diluted with assay buffer [1×HBSSwith calcium/magnesium (Gibco Cat #14025-092), 20 mM HEPES (Gibco Cat#15630-080) and 0.1% fatty acid free BSA (Sigma Cat #A9205)] to a finalconcentration of 0.5% DMSO. Diluted compounds were added to the cells byFDSS6000 (Hamamatsu) at final concentrations ranging from 0.08 nM to 5μM. and were then incubated for 20 min at room temperature at which timeLPA (Avanti Polar Lipids Cat #857130C) was added at final concentrationsof 10 nM to stimulate the cells. The compound IC₅₀ value was defined asthe concentration of test compound which inhibited 50% of the calciumflux induced by LPA alone. IC₅₀ values were determined by fitting datato a 4-parameter logistic equation (GraphPad Prism, San Diego CA).

b. In Vivo AssaysLPA Challenge with Plasma Histamine Evaluation.

Compound is dosed orally p.o. 2 hours to CD-1 female mice prior to theLPA challenge. The mice are then dosed via tail vein (IV) with 0.15 mLof LPA in 0.1% BSA/PBS (2 μg/μL). Exactly 2 minutes following the LPAchallenge, the mice are euthanized by decapitation and the trunk bloodis collected. These samples are collectively centrifuged and individual75 μL samples are frozen at −20° C. until the time of the histamineassay.

The plasma histamine analysis was run by standard EIA (EnzymeImmunoassay) methods. Plasma samples were thawed and diluted 1:30 in0.1% BSA in PBS. The EIA protocol for histamine analysis as outlined bythe manufacturer was followed (Histamine EIA, Oxford BiomedicalResearch, EA #31).

The LPA used in the assay is formulated as follows: LPA(1-oleoyl-2-hydroxy-sn-glycero-3-phosphate (sodium salt), 857130P,Avanti Polar Lipids) is prepared in 0.1% BSA/PBS for total concentrationof 2 μg/μL. 13 mg of LPA is weighed and 6.5 mL 0.1% BSA added, vortexedand sonicated for −1 hour until a clear solution is achieved.

V. Pharmaceutical Compositions, Formulations and Combinations

In some embodiments, provided is a pharmaceutical composition comprisinga therapeutically effective amount of a compound of Formulas (I)-(IX),or a pharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical composition also contains at least one pharmaceuticallyacceptable inactive ingredient.

In some embodiments, provided is a pharmaceutical composition comprisinga therapeutically effective amount of a compound of Formulas (I)-(IX),or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable inactive ingredient. In one aspect, thepharmaceutical composition is formulated for intravenous injection,subcutaneous injection, oral administration, inhalation, nasaladministration, topical administration, ophthalmic administration orotic administration. In some embodiments, the pharmaceutical compositionis a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spraysolution, a suppository, a suspension, a gel, a colloid, a dispersion, asuspension, a solution, an emulsion, an ointment, a lotion, an eye dropor an ear drop.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutically active agents selected from:corticosteroids (e.g., dexamethasone or fluticasone), immunosuppresants(e.g., tacrolimus & pimecrolimus), analgesics, anti-cancer agent,anti-inflammatories, chemokine receptor antagonists, bronchodilators,leukotriene receptor antagonists (e.g., montelukast or zafirlukast),leukotriene formation inhibitors, monoacylglycerol kinase inhibitors,phospholipase A₁ inhibitors, phospholipase A₂ inhibitors, andlysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors,decongestants, antihistamines (e.g., loratidine), mucolytics,anticholinergics, antitussives, expectorants, anti-infectives (e.g.,fusidic acid, particularly for treatment of atopic dermatitis),anti-fungals (e.g., clotriazole, particularly for atopic dermatitis),anti-IgE antibody therapies (e.g., omalizumab), 3-2 adrenergic agonists(e.g., albuterol or salmeterol), other PGD2 antagonists acting at otherreceptors such as DP antagonists, PDE4 inhibitors (e.g., cilomilast),drugs that modulate cytokine production, e.g., TACE inhibitors, drugsthat modulate activity of Th2 cytokines IL-4 & IL-5 (e.g., blockingmonoclonal antibodies & soluble receptors), PPARγ agonists (e.g.,rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (e.g.,zileuton).

In some embodiments, the pharmaceutical composition further comprisesone or more additional anti-fibrotic agents selected from pirfenidone,nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferonalpha, lecithinized superoxide dismutase, simtuzumab, tanzisertib,tralokinumab, hu3G9, AM-152, IFN-gamma-1b, IW-001, PRM-151, PXS-25,pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E, salbutamolsulfate, [Sar9, Met(O2)11]-Substance P, pentoxifylline, mercaptaminebitartrate, obeticholic acid, aramchol, GFT-505, eicosapentaenoic acidethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E,MK-4074, PX-102, RO-5093151. In some embodiments, provided is a methodcomprising administering a compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, to a human with aLPA-dependent or LPA-mediated disease or condition. In some embodiments,the human is already being administered one or more additionaltherapeutically active agents other than a compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof. In someembodiments, the method further comprises administering one or moreadditional therapeutically active agents other than a compound ofFormulas (I)-(IX), or a pharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, are selected from: corticosteroids (e.g.dexamethasone or fluticasone), immunosuppresants (e.g., tacrolimus &pimecrolimus), analgesics, anti-cancer agent, anti-inflammatories,chemokine receptor antagonists, bronchodilators, leukotriene receptorantagonists (e.g., montelukast or zafirlukast), leukotriene formationinhibitors, monoacylglycerol kinase inhibitors, phospholipase A₁inhibitors, phospholipase A₂ inhibitors, and lysophospholipase D(lysoPLD) inhibitors, autotaxin inhibitors, decongestants,antihistamines (e.g., loratidine), mucolytics, anticholinergics,antitussives, expectorants, anti-infectives (e.g., fusidic acid,particularly for treatment of atopic dermatitis), anti-fungals (e.g.,clotriazole, particularly for atopic dermatitis), anti-IgE antibodytherapies (e.g., omalizumab), 3-2 adrenergic agonists (e.g., albuterolor salmeterol), other PGD2 antagonists acting at other receptors such asDP antagonists, PDE4 inhibitors (e.g., cilomilast), drugs that modulatecytokine production, e.g. TACE inhibitors, drugs that modulate activityof Th2 cytokines IL-4 & IL-5 (e.g., blocking monoclonal antibodies &soluble receptors), PPARγ agonists (e.g., rosiglitazone andpioglitazone), 5-lipoxygenase inhibitors (e.g., zileuton).

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, are other anti-fibrotic agents selected frompirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab,interferon alpha, lecithinized superoxide dismutase, simtuzumab,tanzisertib, tralokinumab, hu3G9, AM-152, IFN-gamma-1b, IW-001, PRM-151,PXS-25, pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E,salbutamol sulfate, [Sar9, Met(O2)11]-Substance P, pentoxifylline,mercaptamine bitartrate, obeticholic acid, aramchol, GFT-505,eicosapentyl ethyl ester, metformin, metreleptin, muromonab-CD3,oltipraz, IMM-124-E, MK-4074, PX-102, RO-5093151.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, are selected from ACE inhibitors, ramipril, Allantagonists, irbesartan, anti-arrythmics, dronedarone, PPARα activators,PPARγ activators, pioglitazone, rosiglitazone, prostanoids, endothelinreceptor antagonists, elastase inhibitors, calcium antagonists, betablockers, diuretics, aldosterone receptor antagonists, eplerenone, renininhibitors, rho kinase inhibitors, soluble guanylate cyclase (sGC)activators, sGC sensitizers, PDE inhibitors, PDE5 inhibitors, NO donors,digitalis drugs, ACE/NEP inhibitors, statins, bile acid reuptakeinhibitors, PDGF antagonists, vasopressin antagonists, aquaretics, NHE1inhibitors, Factor Xa antagonists, Factor XIIIa antagonists,anticoagulants, anti-thrombotics, platelet inhibitors, profibroltics,thrombin-activatable fibrinolysis inhibitors (TAFI), PAI-1 inhibitors,coumarins, heparins, thromboxane antagonists, serotonin antagonists, COXinhibitors, aspirin, therapeutic antibodies, GPIIb/IIIa antagonists, ERantagonists, SERMs, tyrosine kinase inhibitors, RAF kinase inhibitors,p38 MAPK inhibitors, pirfenidone, multi-kinase inhibitors, nintedanib,sorafenib.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formulas (I)-(IX), or a pharmaceuticallyacceptable salt thereof, are selected from Gremlin-1 mAb, PA1-1 mAb,Promedior (PRM-151; recombinant human Pentraxin-2); FGF21, TGFβantagonists, αvβ6 & αvβ pan-antagonists; FAK inhibitors, TG2 inhibitors,LOXL2 inhibitors, NOX4 inhibitors, MGAT2 inhibitors, GPR120 agonists.

Pharmaceutical formulations described herein are administrable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular), intranasal, buccal, topical or transdermaladministration routes. The pharmaceutical formulations described hereininclude, but are not limited to, aqueous liquid dispersions,self-emulsifying dispersions, solid solutions, liposomal dispersions,aerosols, solid dosage forms, powders, immediate release formulations,controlled release formulations, fast melt formulations, tablets,capsules, pills, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate and controlled release formulations.

In some embodiments, the compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, is administered orally.

In some embodiments, the compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, is administered topically. Insuch embodiments, the compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, is formulated into a varietyof topically administrable compositions, such as solutions, suspensions,lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks,medicated bandages, balms, creams or ointments. Such pharmaceuticalcompounds can contain solubilizers, stabilizers, tonicity enhancingagents, buffers and preservatives. In one aspect, the compound ofFormulas (I)-(IX), or a pharmaceutically acceptable salt thereof, isadministered topically to the skin.

In another aspect, the compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, is administered by inhalation.In one embodiment, the compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, is administered by inhalationthat directly targets the pulmonary system.

In another aspect, the compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, is formulated for intranasaladministration. Such formulations include nasal sprays, nasal mists, andthe like.

In another aspect, the compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, is formulated as eye drops.

In another aspect is the use of a compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating a disease, disorder or conditions in which theactivity of at least one LPA receptor contributes to the pathologyand/or symptoms of the disease or condition. In one embodiment of thisaspect, the LPA is selected from LPA₁, LPA₂, LPA₃, LPA₄, LPA₅ and LPA₆.In one aspect, the LPA receptor is LPA₁. In one aspect, the disease orcondition is any of the diseases or conditions specified herein.

In any of the aforementioned aspects are further embodiments in which:(a) the effective amount of the compound of Formulas (I)-(IX), or apharmaceutically acceptable salt thereof, is systemically administeredto the mammal; and/or (b) the effective amount of the compound isadministered orally to the mammal; and/or (c) the effective amount ofthe compound is intravenously administered to the mammal; and/or (d) theeffective amount of the compound is administered by inhalation; and/or(e) the effective amount of the compound is administered by nasaladministration; or and/or (f) the effective amount of the compound isadministered by injection to the mammal; and/or (g) the effective amountof the compound is administered topically to the mammal; and/or (h) theeffective amount of the compound is administered by ophthalmicadministration; and/or (i) the effective amount of the compound isadministered rectally to the mammal; and/or (j) the effective amount isadministered non-systemically or locally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Also provided is a method of inhibiting the physiological activity ofLPA in a mammal comprising administering a therapeutically effectiveamount of a compound of Formulas (I)-(IX) or a pharmaceuticallyacceptable salt thereof to the mammal in need thereof.

In one aspect, provided is a medicament for treating a LPA-dependent orLPA-mediated disease or condition in a mammal comprising atherapeutically effective amount of a compound of Formulas (I)-(IX), ora pharmaceutically acceptable salt thereof.

In some cases disclosed herein is the use of a compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a LPA-dependent orLPA-mediated disease or condition.

In some cases disclosed herein is the use of a compound of Formulas(I)-(IX), or a pharmaceutically acceptable salt thereof, in thetreatment or prevention of a LPA-dependent or LPA-mediated disease orcondition.

In one aspect, is a method for treating or preventing a LPA-dependent orLPA-mediated disease or condition in a mammal comprising administering atherapeutically effective amount of a compound of Formulas (I)-(IX), ora pharmaceutically acceptable salt thereof.

In one aspect, LPA-dependent or LPA-mediated diseases or conditionsinclude, but are not limited to, fibrosis of organs or tissues,scarring, liver diseases, dermatological conditions, cancer,cardiovascular disease, respiratory diseases or conditions, inflammatorydisease, gastrointestinal tract disease, renal disease, urinarytract-associated disease, inflammatory disease of lower urinary tract,dysuria, frequent urination, pancreas disease, arterial obstruction,cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy,and fibromyalgia.

In one aspect, the LPA-dependent or LPA-mediated disease or condition isa respiratory disease or condition. In some embodiments, the respiratorydisease or condition is asthma, chronic obstructive pulmonary disease(COPD), pulmonary fibrosis, pulmonary arterial hypertension or acuterespiratory distress syndrome.

In some embodiments, the LPA-dependent or LPA-mediated disease orcondition is selected from idiopathic pulmonary fibrosis; other diffuseparenchymal lung diseases of different etiologies including iatrogenicdrug-induced fibrosis, occupational and/or environmental inducedfibrosis, granulomatous diseases (sarcoidosis, hypersensitivitypneumonia), collagen vascular disease, alveolar proteinosis, langerhanscell granulomatosis, lymphangioleiomyomatosis, inherited diseases(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,metabolic storage disorders, familial interstitial lung disease);radiation induced fibrosis; chronic obstructive pulmonary disease(COPD); scleroderma; bleomycin induced pulmonary fibrosis; chronicasthma; silicosis; asbestos induced pulmonary fibrosis; acuterespiratory distress syndrome (ARDS); kidney fibrosis;tubulointerstitium fibrosis; glomerular nephritis; focal segmentalglomerular sclerosis; IgA nephropathy; hypertension; Alport; gutfibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis;toxic/drug induced liver fibrosis; hemochromatosis; nonalcoholicsteatohepatitis (NASH); biliary duct injury; primary biliary cirrhosis;infection induced liver fibrosis; viral induced liver fibrosis; andautoimmune hepatitis; corneal scarring; hypertrophic scarring; Duputrendisease, keloids, cutaneous fibrosis; cutaneous scleroderma; spinal cordinjury/fibrosis; myelofibrosis; vascular restenosis; atherosclerosis;arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, chroniclymphocytic leukemia, tumor metastasis, transplant organ rejection,endometriosis, neonatal respiratory distress syndrome and neuropathicpain.

In one aspect, the LPA-dependent or LPA-mediated disease or condition isdescribed herein.

In one aspect, provided is a method for the treatment or prevention oforgan fibrosis in a mammal comprising administering a therapeuticallyeffective amount of a compound of Formulas (I)-(IX) or apharmaceutically acceptable salt thereof to a mammal in need thereof.

In one aspect, the organ fibrosis comprises lung fibrosis, renalfibrosis, or hepatic fibrosis.

In one aspect, provided is a method of improving lung function in amammal comprising administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereofto the mammal in need thereof. In one aspect, the mammal has beendiagnosed as having lung fibrosis.

In one aspect, compounds disclosed herein are used to treat idiopathicpulmonary fibrosis (usual interstitial pneumonia) in a mammal.

In some embodiments, compounds disclosed herein are used to treatdiffuse parenchymal interstitial lung diseases in mammal: iatrogenicdrug induced, occupational/environmental (Farmer lung), granulomatousdiseases (sarcoidosis, hypersensitivity pneumonia), collagen vasculardisease (scleroderma and others), alveolar proteinosis, langerhans cellgranulonmatosis, lymphangioleiomyomatosis, Hermansky-Pudlak Syndrome,Tuberous sclerosis, neurofibromatosis, metabolic storage disorders,familial interstitial lung disease.

In some embodiments, compounds disclosed herein are used to treatpost-transplant fibrosis associated with chronic rejection in a mammal:Bronchiolitis obliterans for lung transplant.

In some embodiments, compounds disclosed herein are used to treatcutaneous fibrosis in a mammal: cutaneous scleroderma, Dupuytrendisease, keloids.

In one aspect, compounds disclosed herein are used to treat hepaticfibrosis with or without cirrhosis in a mammal: toxic/drug induced(hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis Bvirus, hepatitis C virus, HCV), nonalcoholic liver disease (NAFLD,NASH), metabolic and auto-immune disease.

In one aspect, compounds disclosed herein are used to treat renalfibrosis in a mammal: tubulointerstitium fibrosis, glomerular sclerosis.

In any of the aforementioned aspects involving the treatment of LPAdependent diseases or conditions are further embodiments comprisingadministering at least one additional agent in addition to theadministration of a compound having the structure of Formulas (I)-(IX),or a pharmaceutically acceptable salt thereof. In various embodiments,each agent is administered in any order, including simultaneously.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

In some embodiments, compounds provided herein are used as antagonistsof at least one LPA receptor. In some embodiments, compounds providedherein are used for inhibiting the activity of at least one LPA receptoror for the treatment of a disease or condition that would benefit frominhibition of the activity of at least one LPA receptor. In one aspect,the LPA receptor is LPA₁.

In other embodiments, compounds provided herein are used for theformulation of a medicament for the inhibition of LPA₁ activity.

Articles of manufacture, which include packaging material, a compound ofFormulas (I)-(IX), or a pharmaceutically acceptable salt thereof, withinthe packaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable salt, tautomers,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, is used for inhibiting the activity of at least one LPAreceptor, or for the treatment, prevention or amelioration of one ormore symptoms of a disease or condition that would benefit frominhibition of the activity of at least one LPA receptor, are provided.

VI. General Synthesis Including Schemes

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al., (Protective Groups in Organic Synthesis,Fourth Edition, Wiley-Interscience (2006)).

The compounds of Formulas (I)-(IX) may be prepared by the exemplaryprocesses described in the following schemes and working examples, aswell as relevant published literature procedures that are used by oneskilled in the art. Exemplary reagents and procedures for thesereactions appear herein after and in the working examples. Protectionand deprotection in the processes below may be carried out by proceduresgenerally known in the art (see, for example, Wuts, P. G. M., Greene'sProtective Groups in Organic Synthesis, 5th Edition, Wiley (2014)).General methods of organic synthesis and functional grouptransformations are found in: Trost, B. M. et al., Eds., ComprehensiveOrganic Synthesis: Selectivity, Strategy & Efficiency in Modern OrganicChemistry, Pergamon Press, New York, NY (1991); Smith, M. B. et al.,March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure. 7th Edition, Wiley, New York, NY (2013); Katritzky, A. R. etal., Eds., Comprehensive Organic Functional Group Transformations II,2nd Edition, Elsevier Science Inc., Tarrytown, N Y (2004); Larock, R.C., Comprehensive Organic Transformations, 2^(nd) Edition, Wiley-VCH,New York, NY (1999), and references therein.

Scheme 1 describes the synthesis of carbamoyloxymethyl triazole-aryloxycyclohexyl acids 14. A dihalo (preferably dibromo) phenyl or azine (e.g.pyridine) derivative 1 is coupled with an appropriately protected (e.g.as a tetrahydropyranyl ether) propargyl alcohol 2 under Sonogashiraconditions (e.g. Alper, P. et al, WO 2008097428) to give thecorresponding bromo-aryl or bromo-heteroaryl protected propargyl alcohol3. Thermal reaction of alkyne 3 with an alkyl azide 4 (with or withoutan appropriate catalyst; Qian, Y. et al, J. Med. Chem., 2012, 55,7920-7939 or Boren, B. C., et al., J. Am. Chem. Soc., 2008, 130,8923-8930) provides the corresponding regioisomeric protectedhydroxylmethyl-triazoles, from which the desired triazole regioisomer 5can be isolated. Reaction of the bromoaryl- or bromoheteroaryl-triazoles5 with pinacol diboronate in the presence of an appropriate palladiumcatalyst (Ishiyama, T. et al, J. Org. Chem. 1995, 60, 7508-7510)provides the corresponding pinacol boronate 6, which is then oxidizedwith hydrogen peroxide to give the corresponding phenol orhydroxyheteroarene 7 (Fukumoto, S. et al, WO 2012137982). Reaction ofphenol/hydroxyheteroarene 7 with a 3-hydroxy cycloalkyl ester 8 underMitsunobu reaction conditions (Kumara Swamy, K. C., Chem. Rev., 2009,109, 2551-2651) furnishes the corresponding triazole cycloalkyl etherester 9. Deprotection of the hydoxytriazole 9 provides the triazolealcohol 10, which is then reacted with 4-nitrophenyl chloroformate inthe presence of an appropriate base to give the corresponding triazole4-nitrophenyl carbonate 11. The triazole 4-nitrophenyl carbonate 11 isthen reacted with an amine 12 in the presence of an appropriate base togive the triazole carbamate 13, which then undergoes ester deprotectionto give the desired carbamoyloxymethyltriazole-aryloxy cycloalkyl acids14.

For the specific example of analogs 14, where R₂═CH₃ (Scheme 1A),instead of using an alkyl azide for the cycloaddition to the protectedhydroxyalkyl alkyne 3, trimethylsilyl azide is a viable replacementreagent (Qian, Y. et al, J. Med. Chem., 2012, 55, 7920-7939) that can beused under either thermal or transition-metal catalyzed conditions(Boren, B. C. et. al., J. Am. Chem. Soc., 2008, 130, 8923-8930). Underthese conditions, the desired triazole regioisomer 15 is obtained as themajor product of the 1,3-dipolar cycloaddition reaction, and thetrimethylsilyl group is subsequently removed under standard desilylationconditions (e.g. Bu₄NF, as in Qian, Y. et al, J. Med. Chem., 2012, 55,7920-7939).

Scheme 2 describes an alternative synthetic route to thecarbamoyloxymethyl triazole-aryloxy cyclohexyl acids 14. A dihalo(preferably dibromo) phenyl or azine (e.g. pyridine) derivative 1 iscoupled with propargyl alcohol under Sonogashira conditions (Alper, P.et al, WO 2008097428) to give the corresponding bromo-aryl orbromo-heteroaryl propargyl alcohol 3. Thermal reaction of alkyne 3 withan alkyl azide 4 (with or without an appropriate catalyst, Qian, Y. etal, J. Med. Chem., 2012, 55, 7920-7939; Boren, B. C. et. al., J. Am.Chem. Soc., 2008, 130, 8923-8930) provides the correspondingregioisomeric hydroxymethyl-triazoles, from which the desired triazoleregioisomer 18 can be isolated. Triazole alcohol 18 is then reacted with4-nitrophenyl chloroformate in the presence of an appropriate base togive the corresponding triazole 4-nitrophenyl carbonate 19, which isthen reacted with an amine 12 in the presence of an appropriate base togive the aryl/heteroaryl-triazole carbamate 20. Thebromo-aryl/heteroaryl triazole 20 is then converted to the hydroxyarylor hydroxy-heteroaryl triazole 21 via the corresponding boronate usingthe 2 step sequence [B(pin)₂/Pd-catalysis followed by treatment withH₂O₂] described in Scheme 1. Hydroxyaryl/heteroaryl triazole 22 is thenreacted with a 3-hydroxy cycloalkylester 8 under Mitsunobu reactionconditions (Kumara Swamy, K. C., Chem. Rev., 2009, 109, 2551-2651) tofurnish the corresponding triazole cycloalkyl ether ester 13 which isthen deprotected to give the desired carbamoyloxy methyltriazole-aryloxycyclohexyl acids 14.

Another alternative synthesis of carbamoyloxymethyl triazole-aryloxycyclohexyl acids 14 is described in Scheme 3. Reaction of analkoxyphenyl or azine (e.g. pyridine) derivative 1 with trimethylsilylacetylene under Sonogashira conditions (Alper, P. et al, WO 2008097428)gives the corresponding alkoxy-aryl or heteroaryl silyl acetylene 23,which is then desilylated under standard conditions (e.g. Bu₄NF) to givethe alkyne 24. Thermal reaction of alkyne 24 with sodium azide gives thecorresponding triazole (Roehrig, U. et al, WO 2009127669), which is thenalkylated with an alkyl iodide 25 under basic conditions to give amixture of regioisomeric alkylated triazoles, from which the desiredtriazole regioisomer 26 can be isolated. Lithiation of triazole 26(Hernandez, M. et al, US 20120115844) followed by reaction with aformylating agent, e.g. dimethyl formamide, provided the triazolealdehyde 27. Deprotection of the alkoxy group of arene/heteroarene 27followed by reprotection of the phenol/hydroxy-heteroarene with a morelabile protecting group (e.g. t-butyldimethylsilyl ether) gives theprotected aryl/heteroaryl triazole aldehyde 28, which is then reduced bystandard methods (e.g. NaBH₄) to the corresponding triazole alcohol 29.Triazole alcohol 29 is reacted with 4-nitrophenyl chloroformate to givethe corresponding triazole 4-nitrophenyl carbonate 30. This triazolecarbonate 30 is then reacted with an amine 12 in the presence of anappropriate base to give the corresponding triazole carbamate, whichsubsequently undergoes deprotection to provide the hydroxyaryl/hetero-aryl triazole carbamate 21. The hydroxy aryl/heteroaryltriazole carbamate 21 then is subjected to a Mitsunobu reaction with3-hydroxy cycloalkyl ester 8 to furnish the corresponding triazolecycloalkyl ether ester 13, followed by ester deprotection to give thedesired carbamoyloxy methyltriazole-aryloxy cyclohexyl acids 14.

A different synthetic route for the preparation of triazole carbamateacids 14 is described in Scheme 4. The protected hydroxyaryl/heteroaryltriazole alcohol 29 is reacted with the intermediate isocyanategenerated from a carboxylic acid 31 under Curtius reaction conditions(Seiders, T. et al, WO 2011041694A2) to give the monoalkyl NH-carbamate32. Base-mediated reaction of NH-carbamate 32 with an appropriate alkyliodide 33 provides the corresponding triazole N-disubstituted carbamate,which is then deprotected to provide the hydroxy aryl/heteroaryltriazole carbamate 21. Hydroxy aryl/heteroaryl triazole carbamate 21then is subjected to a Mitsunobu reaction with 3-hydroxy cycloalkylester8 to furnish the corresponding triazole cycloalkyl ether ester 13followed by ester deprotection to give the desired carbamoyloxymethyltriazole-aryloxy cyclohexyl acids 14. Alternatively, the triazolemonoalkyl NH-carbamate 32 is deprotected to give the hydroxyaryl/heteroaryl triazole carbamate, which is then reacted with 3-hydroxycycloalkylester 8 under Mitsunobu reaction conditions to provide thetriazole-aryloxy cyclohexyl ester NH-carbamate 34. IntermediateNH-carbamate 34 is then alkylated with alkyl iodide 33 under basicconditions; subsequent ester deprotection furnishes the desiredcarbamoyloxy methyltriazole-aryloxy cyclohexyl acids 14.

An alternative synthesis of carbamoyloxy methyltriazole-aryloxycyclohexyl acids 14 from the protected hydroxyalkyltriazole cycloalkylether ester 9 is described in Scheme 5. Selective deprotection of thealcohol of 9 followed by its reaction with the isocyanate generated fromthe Curtius rearrangement of an alkyl carboxylic acid 31 provides thetriazole NH monoalkyl carbamate 34. The triazole NH-carbamate 34 is thenalkylated with alkyl iodide 33 under basic conditions, followed by esterdeprotection to give the desired carbamoyloxy methyltriazole-aryloxycyclohexyl acids 14.

Scheme 6 describes the synthesis of carbamoyloxy methyltriazole-aryloxyα-F cyclohexyl acids 42. Diels-Alder reaction of diene 35 and ethyl2-fluoroacrylate 36 under thermal conditions (e.g. procedure of Kotikyanet al., Bulletin of the Academy of Sciences of the USSR, Division ofChemical Science (Engl.), 1971, 20, 292) gives the α-F cyclohexyl ester37. Hydrolysis of ester 37 under basic condition provides acid 38.Iodolactonization (e.g. Nolspe, J. M. J. et al., Eur. J. Org. Chem.,2014, 3051-3065) of the olefin with the carboxylic acid of 38 givesiodolactone 39. Deiodination under radical condition (e.g.AIBN/(TMS)₃SiH, ref. Chatgilialoglu, C. et al., Molecules, 2012, 17,527-555) affords lactone 40. Openning of lactone 40 via acidic condition(e.g. AcCl in iPrOH) gives the α-F cyclohexyl ester 41. The carbamoyloxymethyltriazole-aryloxy α-F cyclohexyl acids 42 are synthesized from theα-F cyclohexyl ester 41 following the general synthetic proceduredescribed in Schemes 1 or 2.

Scheme 7 describes the synthesis of carbamoyloxy methyltriazole-aryloxycyclohexyl acids 44. Addition of an alkyl organometallic reagent (e.gR₁₃Li or R₁₃MgX) to aldehyde 28 gives triazole alcohol 43. Thecarbamoyloxy methyltriazole-aryloxy cyclohexyl acids 44 can then besynthesized from triazole alcohol 43 following the general syntheticprocedure described in Scheme 3.

Scheme 8 describes the synthesis of carbamoyloxy methyltriazole-aryloxycyclohexyl amides 45, tetrazoles 47 and acyl sulfonamide 48. Treatmentof acid 14 with AcCl followed by ammonia gives primary amide 45.Dehydration of primary amide 45 with Burgess reagent (Talibi, P. et al.,e-EROS Encyclopedia of Reagents for Organic Synthesis, published online15 Sep. 2008, DOI: 10.1002/047084289X.rm095 m.pub2) furnishes nitrile46. Cycloaddition of azide to nitrile 46 affords the tetrazole 47. In asimilar manner to the preparation of amides 45, acyl sulfonamides 48 canbe synthesized by the reaction of carboxylic acid 14 with methylsulfonamide using standard coupling agents (e.g. EDC/DMAP).

Scheme 9 describes the synthesis of carbamoyloxyethyl triazole-aryloxycyclohexyl acids 53. The protected alcohol intermediate 9 is deprotectedto the corresponding alcohol, which is then oxidized to thecorresponding aldehyde (e.g. Dess-Martin periodinane or Swern oxidation)which is then subjected to an olefination reaction (e.g. Witting orPeterson olefination reaction) which provides the terminal olefin 49.Hydroboration of olefin 49 at the terminal carbon (e.g. with 9-BBN),followed by oxidative workup, provides the corresponding triazole ethylalcohol 50. Triazole ethyl alcohol 50 is reacted with 4-nitrophenylchloroformate in the presence of an appropriate base to give thecorresponding triazole 4-nitrophenyl carbonate 51. The triazole4-nitrophenyl carbonate 51 is then reacted with an amine 12 in thepresence of an appropriate base to give the triazole carbamate 52, whichthen undergoes ester deprotection to give the desiredcarbamoyloxyethyltriazole-aryloxy cycloalkyl acids 53.

Scheme 10 describes the synthesis of carbamoyloxypropyl triazole-aryloxycyclohexyl acids 58. The protected alcohol intermediate 9 is deprotectedto the corresponding alcohol, then is oxidized to the correspondingaldehyde which is then subjected to olefination conditions (eg. Wittigreaction with a reagent with an appropriately protected alcohol such as2-(benzyloxy) ethylidene) as shown) which provides olefin 54 as amixture of cis/trans isomers. Hydrogenation of the olefin, followed bydeprotection of the alcohol (e.g. using hydrogenolysis with H₂),provides the corresponding triazole alcohol 55. The triazole alcohol 55is reacted with 4-nitrophenyl chloroformate in the presence of anappropriate base to give the corresponding triazole 4-nitrophenylcarbonate 56. The triazole 4-nitrophenyl carbonate 56 is then reactedwith an amine 12 in the presence of an appropriate base to give thetriazole carbamate 57, which then undergoes ester deprotection to givethe desired carbamoyloxypropyltriazole-aryloxy cycloalkyl acids 58.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “RBF”for round bottom flask, “atm” for atmosphere, “psi” for pounds persquare inch, “conc.” for concentrate, “RCM” for ring-closing metathesis,“sat” or “sat'd” for saturated, “SFC” for supercritical fluidchromatography “MW” for molecular weight, “mp” for melting point, “ee”for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry,“ESI” for electrospray ionization mass spectroscopy, “HR” for highresolution, “HRMS” for high resolution mass spectrometry, “LCMS” forliquid chromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” forthin layer chromatography, “NMR” for nuclear magnetic resonancespectroscopy, “nOe” for nuclear Overhauser effect spectroscopy, “¹H” forproton, “δ” for delta, “s” for singlet, “d” for doublet, “t” fortriplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” forhertz, and “α”, “β”, “γ”, “R”, “S”, “E”, and “Z” are stereochemicaldesignations familiar to one skilled in the art.

-   -   Me methyl    -   Et ethyl    -   Pr propyl    -   i-Pr isopropyl    -   Bu butyl    -   i-Bu isobutyl    -   t-Bu tert-butyl    -   Ph phenyl    -   Bn benzyl    -   Boc or BOC tert-butyloxycarbonyl    -   Boc₂O di-tert-butyl dicarbonate    -   AcOH or HOAc acetic acid    -   AlCl₃ aluminum trichloride    -   AIBN Azobis-isobutyronitrile    -   BBr₃ boron tribromide    -   BCl₃ boron trichloride    -   BEMP        2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine    -   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium        hexafluorophosphate    -   Burgess reagent        1-methoxy-N-triethylammoniosulfonyl-methanimidate    -   CBz carbobenzyloxy    -   DCM or CH₂Cl₂ dichloromethane    -   CH₃CN or ACN acetonitrile    -   CDCl₃ deutero-chloroform    -   CHCl₃ chloroform    -   mCPBA or m-CPBA meta-chloroperbenzoic acid    -   Cs₂CO₃ cesium carbonate    -   Cu(OAc)₂ copper (II) acetate    -   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCE 1,2 dichloroethane    -   DEA diethylamine    -   Dess-Martin        1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one    -   DIC or DIPCDI diisopropylcarbodiimide    -   DIEA, DIPEA or diisopropylethylamine    -   Hunig's base    -   DMAP 4-dimethylaminopyridine    -   DME 1,2-dimethoxyethane    -   DMF dimethyl formamide    -   DMSO dimethyl sulfoxide    -   cDNA complementary DNA    -   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane    -   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene    -   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide    -   EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride    -   EDTA ethylenediaminetetraacetic acid    -   (S,S)-EtDuPhosRh(I)        (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)        trifluoromethanesulfonate    -   Et₃N or TEA triethylamine    -   EtOAc ethyl acetate    -   Et₂O diethyl ether    -   EtOH ethanol    -   GMF glass microfiber filter    -   Grubbs II        (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro        (phenylmethylene)(triycyclohexylphosphine)ruthenium    -   HCl hydrochloric acid    -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid    -   Hex hexane    -   HOBt or HOBT 1-hydroxybenzotriazole    -   H₂O₂ hydrogen peroxide    -   IBX 2-iodoxybenzoic acid    -   H₂SO₄ sulfuric acid    -   Jones reagent CrO₃ in aqueous H₂SO₄, 2 M solution    -   K₂CO₃ potassium carbonate    -   K₂HPO₄ potassium phosphate dibasic (potassium hydrogen        phosphate)    -   KOAc potassium acetate    -   K₃PO₄ potassium phosphate tribasic    -   LAH lithium aluminum hydride    -   LG leaving group    -   LiOH lithium hydroxide    -   MeOH methanol    -   MgSO₄ magnesium sulfate    -   MsOH or MSA methylsulfonic acid/methanesulfonic acid    -   NaCl sodium chloride    -   NaH sodium hydride    -   NaHCO₃ sodium bicarbonate    -   Na₂CO₃ sodium carbonate    -   NaOH sodium hydroxide    -   Na₂SO₃ sodium sulfite    -   Na₂SO₄ sodium sulfate    -   NBS N-bromosuccinimide    -   NCS N-chlorosuccinimide    -   NH₃ ammonia    -   NH₄Cl ammonium chloride    -   NH₄OH ammonium hydroxide    -   NH₄ ⁺HCO₂ ⁻ ammonium formate    -   NMM N-methylmorpholine    -   OTf triflate or trifluoromethanesulfonate    -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(O)    -   Pd(OAc)₂ palladium(II) acetate    -   Pd/C palladium on carbon    -   Pd(dppf)Cl₂        [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)    -   Ph₃PCl₂ triphenylphosphine dichloride    -   PG protecting group    -   POCl₃ phosphorus oxychloride    -   PPTS pyridinium p-toluenesulfonate    -   i-PrOH or IPA isopropanol    -   PS Polystyrene    -   RT or rt room temperature    -   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride    -   SiO₂ silica oxide    -   SnCl₂ tin(II) chloride    -   TBAF tra-n-butylammonium fluoride    -   TBAI tetra-n-butylammonium iodide    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   THP tetrahydropyran    -   TMSCHN₂ Trimethylsilyldiazomethane    -   TMSCH₂N₃ Trimethylsilylmethyl azide    -   T3P propane phosphonic acid anhydride    -   TRIS tris (hydroxymethyl) aminomethane    -   pTsOH p-toluenesulfonic acid

VII. Examples

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

As appropriate, reactions were conducted under an atmosphere of drynitrogen (or argon). For anhydrous reactions, DRISOLV® solvents from EMwere employed. For other reactions, reagent grade or HPLC grade solventswere utilized. Unless otherwise stated, all commercially obtainedreagents were used as received.

HPLC/MS and Preparatory/Analytical HPLC Methods Employed inCharacterization or Purification of Examples

NMR (nuclear magnetic resonance) spectra were typically obtained onBruker or JEOL 400 MHz and 500 MHz instruments in the indicatedsolvents. All chemical shifts are reported in ppm from tetramethylsilanewith the solvent resonance as the internal standard. ¹HNMR spectral dataare typically reported as follows: chemical shift, multiplicity(s=singlet, br s=broad singlet, d=doublet, dd=doublet of doublets,t=triplet, q=quartet, sep=septet, m=multiplet, app=apparent), couplingconstants (Hz), and integration.

In the examples where ¹H NMR spectra were collected in d₆-DMSO, awater-suppression sequence is often utilized. This sequence effectivelysuppresses the water signal and any proton peaks in the same regionusually between 3.30-3.65 ppm which will affect the overall protonintegration.

The term HPLC refers to a Shimadzu high performance liquidchromatography instrument with one of following methods:

HPLC-1: Sunfire C18 column (4.6×150 mm) 3.5 μm, gradient from 10 to 100%B:A for 12 min, then 3 min hold at 100% B.

Mobile phase A: 0.05% TFA in water:CH₃CN (95:5)

Mobile phase B: 0.05% TFA in CH₃CN:water (95:5)

TFA Buffer pH=2.5; Flow rate: 1 mL/min; Wavelength: 254 nm, 220 nm.

HPLC-2: XBridge Phenyl (4.6×150 mm) 3.5 μm, gradient from 10 to 100% B:Afor 12 min, then 3 min hold at 100% B.

Mobile phase A: 0.05% TFA in water:CH₃CN (95:5)

Mobile phase B: 0.05% TFA in CH₃CN:water (95:5)

TFA Buffer pH=2.5; Flow rate: 1 mL/min; Wavelength: 254 nm, 220 nm.

HPLC-3: Chiralpak AD-H, 4.6×250 mm, 5 μm.

Mobile Phase: 30% EtOH-heptane (1:1)/70% CO₂

Flow rate=40 mL/min, 100 Bar, 35° C.; Wavelength: 220 nm

HPLC-4: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;

Mobile Phase A: 5:95 CH₃CN:water with 10 mM NH₄OAc;

Mobile Phase B: 95:5 CH₃CN:water with 10 mM NH₄OAc;

Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B;

Flow: 1.11 mL/min; Detection: UV at 220 nm.

HPLC-5: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;

Mobile Phase A: 5:95 CH₃CN:water with 0.1% TFA;

Mobile Phase B: 95:5 CH₃CN:water with 0.1% TFA;

Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

Intermediate 1 (±)-cis-isopropyl1-fluoro-3-hydroxycyclohexanecarboxylate

Intermediate 1A (±)-ethyl 1-fluorocyclohex-3-enecarboxylate

A mixture of 20% buta-1,3-diene in toluene (13.8 mL, 41.1 mmol) andethyl 2-fluoroacrylate (3.07 mL, 27.4 mmol) was heated at 120° C. in asealed tube for 7 days. The reaction was cooled to rt and concentratedin vacuo. The residue was chromatographed (80 g SiO₂) with EtOAc/Hexane(continuous gradient from 0% to 10% EtOAc over 20 min) to giveIntermediate 1A (3.80 g, 22.1 mmol, 80% yield) as a clear oil. ¹H NMR(500 MHz, CDCl₃) δ 5.79 (ddd, J=9.9, 4.7, 2.2 Hz, 1H), 5.64-5.58 (m,1H), 4.26 (q, J=7.2 Hz, 2H), 2.73-2.57 (m, 1H), 2.45-2.23 (m, 2H),2.20-1.91 (m, 3H), 1.32 (t, J=7.2 Hz, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ−162.69 (s, 1F).

Intermediate 1B (±)-1-fluorocyclohex-3-ene carboxylic acid

A mixture of Intermediate 1A (3.80 g, 22.1 mmol) and aq. LiOH (55.2 mLof a 2.0 M solution, 110 mmol) in THF (50 mL) was stirred at rt for 18h. The reaction was acidified to pH=2 with conc. HCl (9.19 mL, 110mmol), and then extracted with EtOAc (3×25 mL). The combined organicextracts were washed with water and concentrated in vacuo to giveIntermediate 1B (3.0 g, 20.8 mmol, 94% yield) as a light yellowish oil.¹H NMR (500 MHz, CDCl₃) δ 5.81 (ddd, J=9.8, 4.6, 2.1 Hz, 1H), 5.66-5.58(m, 1H), 2.76-2.59 (m, 1H), 2.49-2.37 (m, 1H), 2.35-2.23 (m, 1H),2.22-1.92 (m, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ −163.02 (s, 1F).

Intermediate 1C (±)-1-fluoro-4-iodo-6-oxabicyclo[3.2.1]octan-7-one

To a mixture of Intermediate 1B (3.0 g, 20.8 mmol) in water (20 mL) wasadded NaHCO₃ (5.25 g, 62.4 mmol) portionwise and the mixture was stirreduntil it became homogeneous. An aq. I₂ solution (prepared by dissolvingI₂ (5.81 g, 22.0 mmol) and KI (20.7 g, 125 mmol) in 20 mL water) wasadded and the reaction was stirred overnight at rt in the dark. Water(100 mL) was then added and the mixture was extracted with DCM (3×25mL), washed with 10% aq. Na₂S₂O₃ (20 mL×2) and water, dried (MgSO₄) andconcentrated in vacuo. The residual crude oil was chromatographed (80 gSiO₂) with EtOAc/Hexane (continuous gradient from 0% to 50% EtOAc over20 min) to give Intermediate 1C (3.53 g, 13.1 mmol, 62.8% yield) as awhite solid. ¹H NMR (500 MHz, CDCl₃) δ 4.89 (dt, J=6.5, 3.5 Hz, 1H),4.44 (q, J=4.6 Hz, 1H), 3.08 (dd, J=11.6, 1.9 Hz, 1H), 2.75 (tddd,J=11.3, 6.5, 3.3, 1.1 Hz, 1H), 2.50-2.38 (m, 1H), 2.34-2.17 (m, 2H),2.11-1.99 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 172.2, 172.0, 93.6, 91.9,78.4, 78.3, 39.2, 39.0, 29.7, 29.6, 28.4, 28.2, 20.2; ¹⁹F NMR (471 MHz,CDCl₃) δ −167.97 (s, 1F)

Intermediate 1D (±)-1-fluoro-6-oxabicyclo[3.2.1]octan-7-one

To a solution of intermediate 1C (350 mg, 1.30 mmol) and AIBN (21 mg,0.130 mmol) in benzene (5 mL) was added tris(trimethylsilyl)silane (0.60mL, 1.94 mmol) portionwise over 10 min at 60° C. The reaction wasstirred at 70° C. for 2 h, cooled to rt and then concentrated in vacuo.The residue was dissolved in EtOAc, washed with sat. aq. NH₄Cl, dried(MgSO₄) and concentrated in vacuo. The crude oil was chromatographed (12g SiO₂) with EtOAc/Hexane (continuous gradient from 0% to 30% EtOAc over10 min) to give Intermediate 1D (124 mg, 0.860 mmol, 66.4% yield) as awhite solid. ¹⁹F NMR (471 MHz, CDCl₃) δ −167.01 (s, 1F); ¹H NMR (500MHz, CDCl₃) δ 4.98-4.81 (m, 1H), 2.75 (dtdd, J=15.9, 6.8, 3.3, 1.7 Hz,1H), 2.24-1.89 (m, 5H), 1.82-1.65 (m, 1H), 1.60-1.46 (m, 1H); ¹³C NMR(126 MHz, CDCl₃) δ 173.2, 173.0, 93.9, 92.3, 75.6, 75.5, 42.0, 41.9,31.3, 31.1, 26.7, 17.7, 17.6

Intermediate 1

Acetyl chloride (0.061 mL, 0.860 mmol) was added portionwise toisopropanol (3 mL) at 0° C. and then stirred at rt for 30 min.Intermediate 1D (124 mg, 0.860 mmol) was added and the reaction wasstirred overnight at rt, then was concentrated in vacuo. The residualcrude oil was chromatographed (4 g SiO₂) with EtOAc/Hexane (continuousgradient from 0% to 50% EtOAc over 10 min) to give Intermediate 1 (140mg, 0.685 mmol, 80% yield) as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ5.08 (spt, J=6.3 Hz, 1H), 3.91 (tt, J=10.9, 4.4 Hz, 1H), 2.68 (br. s.,1H), 2.28 (dddt, J=13.5, 9.0, 4.6, 2.1 Hz, 1H), 2.06-1.98 (m, 1H),1.96-1.87 (m, 1H), 1.82-1.62 (m, 4H), 1.37-1.22 (m, 7H); ¹⁹F NMR (471MHz, CDCl₃) δ −162.93 (s, 1F); ¹³C NMR (126 MHz, CDCl₃) δ 170.9, 170.7,95.7, 94.2, 69.3, 66.1, 40.7, 40.5, 33.9, 31.6, 31.4, 21.5, 19.1

Intermediate 2 isopropyl (3R)-3-hydroxycyclohexane-1-carboxylate-1-d

Intermediate 2A isopropyl(1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate

To a solution of (1S,3R)-isopropyl 3-hydroxycyclohexanecarboxylate (0.5g, 2.68 mmol) and imidazole (0.238 g, 3.49 mmol) in DCM (4 mL) was addedtert-butylchlorodimethylsilane (0.486 g, 3.22 mmol) in DCM (1 mL)dropwise over 5 min, stirred at rt overnight. The reaction was dilutedwith Et₂O (20 mL). The mixture was washed with brine (10 mL); the whiteaqueous phase was separated and the organic phase was washed with water(10 mL), dried over Na₂SO₄ and concentrated in vacuo. The crude oil waschromatographed (80 g SiO₂) using a gradient of EtOAc/Hexane (0% to 20%over 15 min) to give (1S,3R)-isopropyl3-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (0.60 g, 1.897mmol, 70.7% yield) as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 5.08-4.95(m, 1H), 3.65-3.51 (m, 1H), 2.40-2.21 (m, 1H), 2.09 (d, J=12.7 Hz, 1H),1.94-1.76 (m, 3H), 1.50-1.35 (m, 1H), 1.34-1.17 (m, 9H), 0.91 (s, 9H),0.13-0.05 (m, 6H)

Intermediate 2B isopropyl(1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate

A solution of LDA (1.664 ml, 3.33 mmol) was added under Ar to a solutionof intermediate 2A (0.5 g, 1.66 mmol) in THF (6.66 mL) at −78° and theresultant mixture was stirred for 60 min. Then D₂O (0.90 mL, 49.9 mmol)was added and the reaction was allowed to warm to rt. Saturated aq.NH₄Cl (3 mL) was added and the solution was allowed to warm to rt. Thereaction mixture was extracted with EtOAc (10 mL), and the combinedorganic extracts were washed with aq. HCl (10 mL of a 2 M solution),saturated aq. NaHCO₃ and then brine. The organic layer was dried overMgSO₄, filtered, then concentrated in vacuo to give an oil as the crudeproduct (used in the next step without further purification)(1S,3R)-isopropyl 3-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate(0.50 g, 1.66 mmol). LCMS, [M+H]⁺=302.1.

Intermediate 2

To a solution of intermediate 2B (0.53 g, 1.758 mmol) in THF (3 mL) wasadded Bu₄NF (3.52 mL of a 1 M solution, 3.52 mmol) at rt and stirredovernight. The reaction was then quenched with 1.5 M aq. potassiumphosphate (10 mL) and extracted with EtOAc (10 mL). The organic extractwas concentrated in vacuo and chromatographed (24 g SiO₂, continuousgradient from 0 to 100% EtOAc/Hexanes over 30 min, then at 100% EtOAcfor 10 min) to give intermediate 2 (0.17 g, 0.908 mmol, 51.6% yield). ¹HNMR (500 MHz, CDCl₃) δ 5.02 (dt, J=12.6, 6.2 Hz, 1H), 4.11 (t, J=4.3 Hz,1H), 1.84 (d, J=4.1 Hz, 3H), 1.77-1.68 (m, 1H), 1.65-1.49 (m, 5H), 1.24(d, J=6.3 Hz, 6H).

Example 1(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

1A3-bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine

To a solution of 2,5-dibromo-6-methyl-pyridine (5 g, 21.11 mmol) and2-(prop-2-yn-1-yloxy) tetrahydro-2H-pyran (4.44 g, 31.7 mmol) in MeCN(42.2 mL) was added Et₃N (8.83 mL, 63.3 mmol). The solution was degassedunder N₂, then trans-dichlorobis (triphenylphosphine) palladium (II)chloride (0.74 g, 1.06 mmol) and CuI (0.20 g, 1.06 mmol) were added. Thereaction was stirred at rt for 14 h, after which the reaction mixturewas filtered through a Celite© plug and the plug was washed with EtOAc(2×10 mL). The filtrate was concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 0% to 100% EtOAc inHexanes for 20 min) to give the title compound as a white solid (6.0 g,20.3 mmol, 96% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J=2.0 Hz, 1H),7.80 (dd, J=8.3, 2.3 Hz, 1H), 7.35 (dd, J=8.4, 0.4 Hz, 1H), 4.91 (t,J=3.3 Hz, 1H), 4.61-4.45 (m, 2H), 3.98-3.81 (m, 1H), 3.66-3.44 (m, 1H),1.92-1.73 (m, 2H), 1.72-1.52 (m, 2H). LCMS, [M+H]⁺=298.0.

1B3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine

A solution of 1A (6.0 g, 20.3 mmol) in toluene (20 mL) and TMSCH₂N₃(7.85 g, 60.8 mmol) was heated at 90° C. under Ar for 15 h, then wascooled to rt. Volatiles were removed in vacuo and the residue wasdissolved in THF (20 mL). To the mixture was added TBAF (20.3 mL of a 1M solution in THF, 20.3 mmol) at 0° C. After stirring for 10 min, thereaction was complete as determined by analytical HPLC. Volatiles wereremoved in vacuo and the residue was chromatographed (SiO₂, continuousgradient from 0% to 100% EtOAc in hexanes over 20 min) to give the titlecompound (2.1 g, 29% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.85 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.03(br. s., 1H), 5.39-5.23 (m, 4H), 4.81-4.76 (m, 1H), 4.17 (s, 3H), 3.91(ddd, J=11.3, 7.9, 3.3 Hz, 1H), 3.65-3.48 (m, 1H), 2.54 (s, 3H),1.88-1.68 (m, 2H), 1.56 (br. s., 2H)

Alternatively, 1B can be synthesized by the following procedure:

To a stirred solution of 1A (4.0 g, 13.5 mmol) in DMF (45 mL) under N₂was added NaN₃ (2.63 g, 40.5 mmol). The reaction mixture was stirred at90° C. for 36 h, then was cooled to rt and filtered through Celite®. Tothe filtrate was added K₂CO₃ (3.73 g, 27.0 mmol) and the reactionmixture was stirred at rt for 10 min. CH₃I (1.27 mL, 20.3 mmol) wasadded dropwise and the reaction mixture was stirred at rt for 16 h, thenwas diluted with water (150 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered and concentratedin vacuo. The residual mixture of products (the 2 N-methyl triazoleregioisomers) were separated by flash chromatography (40 g Redisep® SiO₂column, eluting with 21% EtOAc in hexanes). The desired regioisomerproduct, title compound 1B, was isolated as a white solid (1.0 g, 21%).LC-MS, [M+2]⁺=355.2. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.64 (d, J=2.0 Hz,1H), 8.10 (d, J=8.0 Hz, 1H), 7.83-7.92 (m, 1H), 5.27 (s, 2H), 4.68-4.77(m, 1H), 4.17 (s, 3H), 3.80-3.90 (m, 1H), 3.49-3.57 (m, 1H), 1.67-1.80(m, 2H), 1.56-1.62 (m, 2H), 1.49-1.55 (m, 2H).

1C2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol

To a degassed solution (sparged with Ar 3X) of 1B (213 mg, 0.60 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (230 mg, 0.91mmol) and KOAc (178 mg, 1.81 mmol) in THF was added Pd(dppf)Cl₂ (22 mg,0.03 mmol). The reaction mixture was heated in a sealed tube at 80° C.for 16 h, then was cooled to rt and partitioned between water and EtOAc.The aqueous layer was extracted with EtOAc (3×20 mL). The combinedorganic extracts were washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. The crude boronate product was carried on to thenext step without further purification. To a solution of the crudeproduct,2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(241 mg, 0.603 mmol) in EtOAc (2 mL) was added H₂O₂ (0.19 mL of a 30%aqueous solution, 6.0 mmol). The reaction mixture was stirred at rt for1 h, then was cooled to 0° C. and quenched by slowly adding sat. aq.Na₂S₂O₃. The aqueous layer was extracted with EtOAc (3×20 mL). Thecombined organic extracts were washed with brine, dried (MgSO₄),filtered and concentrated in vacuo. The residue was chromatographed(SiO₂, continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) togive the title compound (150 mg, 86%) as as a white solid. ¹H NMR (400MHz, CDCl₃) δ 8.27 (d, J=2.6 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.29-7.21(m, 1H), 5.33 (s, 1H), 5.28 (d, J=2.4 Hz, 2H), 4.76 (s, 1H), 4.18 (s,3H), 3.90 (s, 1H), 3.63-3.48 (m, 1H), 1.72 (s, 2H), 1.65-1.51 (m, 2H).LCMS, [M+H]⁺=291.2.

1D. isopropyl(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of 1C (1.18 g, 4.06 mmol) and (1S, 3R)-isopropyl 3-hydroxycyclohexanecarboxylate (synthesized according to the procedure describedin US2007/0197788A1, 1.51 g, 8.13 mmol) in toluene (81 mL) was addedBusP (3.17 mL, 12.2 mmol). To this stirred mixture was added(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (3.08 g, 12.2 mmol)portionwise, and the reaction mixture was heated at 50° C. for 120 min,then was cooled to rt. At this point an LC-MS of the reaction mixtureshowed the presence of the desired product. The mixture was filtered andthe filtrate was concentrated in vacuo. The residue was chromatographed(SiO₂, continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) togive the title compound (1.20 g, 2.62 mmol, 64.4% yield) as a whitefoam. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.6 Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.45-5.24 (m, 2H), 5.04 (dt, J=12.5, 6.3 Hz, 1H), 4.83-4.64 (m,2H), 4.16 (s, 3H), 3.91 (ddd, J=11.2, 7.9, 3.1 Hz, 1H), 3.64-3.48 (m,1H), 2.93-2.71 (m, 1H), 2.52 (s, 3H), 2.23-1.45 (m, 14H), 1.26 (dd,J=6.4, 2.0 Hz, 6H).

1E. isopropyl(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of 1D (1.7 g, 3.71 mmol) in MeOH (37 mL) added pyridiniump-toluenesulfonate (0.932 g, 3.71 mmol). The reaction mixture was heatedto 60° C. for 2 h, then was cooled to rt, diluted with water and sat.aq. NaHCO₃, then extracted with EtOAc (3×10 mL). The combined organicextracts were concentrated in vacuo and chromatographed (SiO₂;continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to givethe title compound as a white foam (1.36 g, 3.63 mmol, 98% yield). ¹HNMR (400 MHz, CDCl₃) δ 8.01 (d, J=8.6 Hz, 1H), 7.46 (d, J=5.1 Hz, 1H),7.27-7.15 (m, 1H), 4.96 (dt, J=12.5, 6.3 Hz, 1H), 4.74 (s, 2H),4.66-4.59 (m, 1H), 4.00 (s, 3H), 2.80-2.64 (m, 1H), 2.46 (s, 3H),2.07-1.50 (m, 8H), 1.18 (dd, J=6.4, 2.2 Hz, 6H).

1F. isopropyl(1S,3S)-3-((2-methyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of 1E (1.36 g, 3.63 mmol) and 4-nitrophenyl chloroformate(2.20 g, 10.9 mmol) in DCM (36.3 mL) was added pyridine (1.47 mL, 18.2mmol). The reaction mixture was stirred at rt for 2 h. LCMS showed thedesired product at this point. The mixture was filtered and the filtratewas concentrated in vacuo. The residue was chromatographed (SiO₂,continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) to affordthe title compound as a white solid (1.66 g, 3.08 mmol, 85% yield). ¹HNMR (400 MHz, CDCl₃) δ 8.30 (d, J=9.2 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H),7.41 (d, J=9.2 Hz, 2H), 7.25 (d, J=8.6 Hz, 1H), 6.07 (s, 2H), 5.05(quin, J=6.2 Hz, 1H), 4.72 (br. s., 1H), 4.22 (s, 3H), 2.91-2.73 (m,1H), 2.52 (s, 3H), 2.21-1.61 (m, 9H), 1.27 (dd, J=6.3, 1.9 Hz, 6H).

1G. isopropyl(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of 1F (5 g, 9 μmmol) and DIPEA (1.5 μL, 9 μmmol) in THF(0.5 mL) was added N-methylcyclopentanamine (1 mg, 9 μmmol). Thereaction mixture was stirred at rt overnight, after which LC-MS showedthe desired product. Volatiles were removed in vacuo and the residue wasdissolved in EtOAc and washed with aq. 1N NaOH (5×10 mL) until theyellow color had disappeared. The organic layer was concentrated invacuo. The residue was used for the next step without purification.LCMS, [M+H]⁺ 514.4.

Example 1

To a stirred solution of 1G (4.6 mg, 9 μmol) in THF (0.5 mL), MeOH (0.1mL) and water (0.1 mL) at rt was added aq LiOH·H₂O (0.023 mL of a 2.0 Msolution, 0.045 mmol). The reaction mixture was stirred at 50° C. for 2h, after which LC-MS showed that all starting material had beenconsumed. The mixture was acidified to pH=−1 by dropwise addition of 1Maq. HCl. The mixture was extracted with EtOAc (3×15 mL); the combinedorganic extracts were concentrated in vacuo. The residue was purified bypreparative HPLC (PHENOMENEX®, Axia 5μ C18 30×100 mm column; detectionat 220 nm; flow rate=40 mL/min; continuous gradient from 0% B to 100% Bover 10 min+2 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) (to give the title compound as an oil (3.2mg, 75%). LCMS, [M+H]⁺ 472.3. ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J=8.2Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.64 (br. s., 2H), 4.79 (br. s., 1H),4.10 (s, 3H), 2.66 (br. s., 4H), 2.42 (s, 3H), 2.10-1.31 (m, 17H). hLPA1IC₅₀=24 nM. Acute in vivo histamine assay in CD-1 mice: −97% histamineat a 3 mg/kg dose of Example 1.

Example 2(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

2A. 3-(5-bromopyridin-2-yl)prop-2-yn-1-ol

To a solution of 3,6-dibromopyridine (25.0 g, 100 mmol)) andprop-2-yn-1-ol (8.70 mL, 149 mmol) in MeCN (141 mL) was added Et₃N (33.2mL, 240 mmol). The solution was degassed under Ar (sparged with Ar 3×),after which trans-dichlorobis(triphenlyphosphine) palladium (II)chloride (2.96 g, 4.22 mmol) and CuI (0.804 g, 4.22 mmol) were added.The reaction was stirred at rt under Ar for 14 h; the mixture wasfiltered through a Celite® plug, which was washed with EtOAc (3×50 mL).The combined filtrates were concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 0% to 100% EtOAc inHexanes, 20 min) to give the title compound as a white solid (16.6 g,74% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.60 (d, J=2.2 Hz, 1H), 7.99 (dd,J=8.4, 2.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 4.41 (s, 2H)

2B (4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

To a degassed (sparged with Ar 3×) solution of 2A (1.9 g, 8.40 mmol) indioxane (42.0 mL) was added chloro(pentamethylcyclopentadienyl)bis(triphenyl-phosphine) ruthenium (II) (0.402 g, 0.504 mmol). The mixturewas degassed 3 times under Ar again and TMSCH₂N₃ (1.87 mL, 12.6 mmol)was added. The reaction was stirred at 50° C. for 15 h under Ar, thencooled to rt and concentrated in vacuo. The oily residue was dissolvedin THF (90 mL) and cooled to 0° C. TBAF (5.40 mL of a 1.0 M solution inTHF; 5.40 mmol) was added and the reaction was stirred at 0° C. for 10min, after which solid NaHCO₃ (4 g) was added. The reaction mixture wasstirred for 30 min at rt and then filtered. The filtrate wasconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the titlecompound (1.30 g, 4.59 mmol, 102% yield) as a white solid. ¹H NMR (500MHz, CDCl₃) δ 8.49 (dd, J=2.3, 0.7 Hz, 1H), 8.08 (dd, J=8.5, 0.6 Hz,1H), 7.83 (dd, J=8.5, 2.2 Hz, 1H), 6.16 (t, J=6.9 Hz, 1H), 4.68 (d,J=6.9 Hz, 2H), 3.95 (s, 3H).

2C (4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl(4-nitrophenyl) carbonate

To a solution of 2B (1.22 g, 4.31 mmol) in CH₂Cl₂ (50 mL) was addedpyridine (1.74 mL, 21.55 mmol) and 4-nitrophenyl chloroformate (1.74 g,8.62 mmol). The reaction was stirred at rt for 1 h, then wasconcentrated in vacuo. The residual solid was triturated with CH₂Cl₂ andfiltered to give the pure title compound. The filtrate was concentratedin vacuo and the residue was chromatographed (SiO₂; continuous gradientfrom 0% to 100% EtOAc in DCM, 20 min); this purified material wascombined with the previously triturated compound to give the titlecompound as a white solid (1.66 g, 86%). LCMS, [M+H]⁺=434.1.

2D. (4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methylcyclopentyl(methyl)carbamate

To a solution of 2C (140 mg, 0.31 mmol) in THF (6.2 mL) was addediPr₂NEt (109 μL, 0.62 mmol) and 1-cyclobutyl-N-methylmethanamine (31 mg,0.31 mmol). The reaction was stirred at rt for 2 h, then wasconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the titlecompound as a white solid (100 mg, 78%). ¹H NMR (400 MHz, CDCl₃) δ 8.66(dd, J=2.4, 0.7 Hz, 1H), 8.11 (dd, J=8.6, 0.7 Hz, 1H), 7.89 (dd, J=8.6,2.4 Hz, 1H), 5.74 (s, 2H), 4.15 (s, 3H), 2.88-2.59 (m, 3H), 1.87-1.38(m, 9H)

2E. (4-(5-Hydroxypyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate

To a degassed (sparged with Ar 3×) solution of 2D (151 mg, 3.70 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.41 g,5.55 mmol), and potassium acetate (1.45 g, 14.8 mmol) in THF (25 mL) wasadded Pd(dppf)Cl₂ (0.271 g, 0.370 mmol) and the reaction was heated at60° C. overnight under Ar, then cooled to rt. Water (10 mL) was addedand the mixture was extracted with EtOAc (2×20 mL). The combined organicextracts were washed with water (10 mL) and brine (10 mL), dried (MgSO₄)and concentrated in vacuo. The residual crude boronate product wasdissolved in EtOAc (15 mL) and H₂O₂ (1.62 mL of a 30% aq. solution, 18.5mmol) was carefully added portionwise at 0° C. The reaction was allowedto warm to rt and stirred at rt for 1 h, then was cooled 0° C. andquenched with sat. aq. Na₂S₂O₃ (20 mL) and extracted with EtOAc (3×20mL). The combined organic extracts were washed with water (20 mL) andbrine (20 mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 0% to 100% EtOAc inHexanes, 20 min) to give the title compound as a white solid (962 mg,75%). ¹H NMR (400 MHz, CD₃OD) δ 8.22 (dd, J=3.0, 0.6 Hz, 1H), 7.87 (dd,J=8.6, 0.7 Hz, 1H), 7.30 (dd, J=8.7, 3.0 Hz, 1H), 5.68 (s, 2H), 4.19 (s,3H), 2.76 (br. s., 3H), 1.92-1.43 (m, 8H). LCMS, [M+H]⁺=332.3.

1G. isopropyl(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of 2E (962 mg, 2.79 mmol), (1S,3R)-isopropyl3-hydroxy-cyclohexanecarboxylate (934 mg, 5.01 mmol), and Bu₃P (1.74 mL,6.96 mmol) in toluene (55 mL) was added(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (1.76 g, 6.96 mmol).The reaction was heated at 50° C. for 7 h, then was cooled to rt. Themixture was diluted with CH₂Cl₂ (20 mL) and filtered through Celite©,which was washed with additional CH₂Cl₂ (3×20 mL). The combinedfiltrates were concentrated in vacuo, and the residue waschromatographed (SiO₂; continuous gradient from 0% to 100% EtOAc inHexanes, 20 min) to give the title compound as a white solid (786 mg,55%). ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J=2.6 Hz, 1H), 8.12 (d, J=8.6Hz, 1H), 7.34 (dd, J=8.8, 2.9 Hz, 1H), 5.78 (s, 2H), 5.05 (dt, J=12.5,6.3 Hz, 1H), 4.77-4.66 (m, 1H), 4.16 (s, 3H), 2.95-2.64 (m, 4H),2.12-2.08 (m, 1H), 2.03-1.87 (m, 4H), 1.82-1.41 (m, 12H), 1.29-1.19 (m,6H). LCMS, [M+H]⁺=500.4.

Example 2

To a solution of 2F (786 mg, 1.53 mmol) in THF (3 mL) and MeOH (3 mL)added aq. LiOH (3.06 mL of a 2N solution, 6.12 mmol). The reactionmixture was stirred at rt overnight, after which the pH was adjusted to˜5 and water (10 mL) was added. The mixture was extracted with EtOAc(3×30 mL), washed with water (30 mL) and brine (30 mL), dried (MgSO₄)and concentrated in vacuo. The resulting solid was dissolved in 3 mL ofEtOAc and allowed to stand overnight to give the title compound as awhite crystalline solid (600 mg, 83%). LCMS, [M+H]⁺=458.2. ¹H NMR (500MHz, CD₃CN) δ 8.34 (d, J=2.5 Hz, 1H), 8.08-8.00 (m, 1H), 7.45 (dd,J=8.8, 2.8 Hz, 1H), 5.66 (s, 2H), 4.88-4.73 (m, 1H), 4.11 (s, 3H),2.87-2.77 (m, 1H), 2.72 (br. s., 3H), 2.10-2.01 (m, 1H), 1.92-1.80 (m,3H), 1.79-1.57 (m, 9H), 1.56-1.43 (m, 4H). HPLC-1: RT=7.99 min,purity=100%; HPLC-2: RT=7.81 min, purity=100%. hLPA1 IC₅₀=19 nM.

Example 3(1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

3A. Isopropyl(1S,3S)-3-((6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

The title compound was prepared by the same synthetic sequence as forExample 1F, except that 2,5-dibromo-pyridine was used as startingmaterial instead of 2,5-dibromo-6-methyl-pyridine. ¹H NMR (400 MHz,CDCl₃) δ 8.43-8.25 (m, 3H), 8.23-8.10 (m, 1H), 7.47-7.31 (m, 3H),6.11-5.77 (m, 2H), 5.20-4.95 (m, 1H), 4.79-4.63 (m, 1H), 4.31-4.19 (m,3H), 2.92-2.71 (m, 1H), 2.12-1.54 (m, 8H), 1.35-1.20 (m, 6H). LCMS,[M+H]+=540.2.

3B. isopropyl(1S,3S)-3-((6-(5-((((2-cyclopropylethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of Example 3A (10 mg, 9.3 μmol) and iPr₂NEt (6.5 μL, 0.037mmol) in THF (0.5 mL) was added 2-cyclopropyl ethanamine (0.8 mg, 9.3μmol). The reaction mixture was stirred at rt overnight, then wasconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 0% to 100% EtOAc in Hexanes, 20 min) to give the titlecompound as a white solid (8 mg, 80%). LCMS, [M+H]+=486.4.

3B. isopropyl(1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of 3A (50 mg, 0.103 mmol) and Mel (0.129 mL, 0.257 mmol)in DMF (0.5 mL) was added NaH (10 mg of a 40% suspension in oil, 0.25mmol). The reaction was stirred at rt for 1 h, then was quenched withwater (5 mL) and extracted with EtOAc (3×10 mL). The combined organicextracts were washed with water (10 mL) and brine (10 mL), dried (MgSO₄)and concentrated in vacuo to give the crude product, which was used inthe next step without further purification. LCMS, [M+H]+=500.4.

Example 3

To a stirred solution of 3B (5 mg, 10 μmol) in THF (1.5 mL), MeOH (0.10mL) and water (0.15 mL) at rt was added aq. LiOH (0.015 mL of a 2 Msolution, 0.030 mmol). The reaction mixture was stirred at 50° C. for 1h, then was cooled to rt. The mixture was acidified to pH 2.3 bydropwise addition of 1M aq. HCl, then was concentrated in vacuo. Theresidue was purified by preparative HPLC (PHENOMENEX®, Axia 5p C1830×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuousgradient from 0% B to 100% B over 10 min+2 min hold time at 100% B,where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) (to givethe title compound as an oil (4.2 mg, 92%). ¹H NMR (500 MHz, DMSO-66) δ8.13 (br. s., 1H), 7.78 (d, J=8.2 Hz, 1H), 7.33 (d, J=6.4 Hz, 1H),5.48-5.30 (m, 2H), 4.57 (br. s., 1H), 3.89 (br. s., 3H), 3.09-2.88 (m,2H), 2.56 (d, J=16.8 Hz, 4H), 2.46 (br. s., 1H), 1.80-1.53 (m, 5H),1.51-1.25 (m, 5H), 1.20-0.93 (m, 4H). LCMS, [M+H]+=458.4. HPLC-4:RT=1.42 min, purity=100%. hLPA1 IC₅₀=19 nM.

Example 4(rac)-trans-3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylicacid

4A Methyl 4-(4-bromophenyl)-1H-1,2,3-triazole-5-carboxylate

To a stirred solution of 4-bromobenzaldehyde (1.0 g, 5.40 mmol), methyl2-cyanoacetate (0.536 g, 5.40 mmol) and Et₃N·HCl (2.23 g, 16.2 mmol) inDMF (20 mL) under N₂ was added NaN₃ (1.12 g, 17.3 mmol) and the reactionmixture was stirred at 70° C. for 16 h, then was cooled to rt. Thereaction mixture was slowly poured into water (100 mL) and extractedwith EtOAc (2×50 mL). The combined organic layer was washed with brine(100 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct was chromatographed (12 g Redisep® SiO₂ column, eluting with 40%EtOAc in n-hexanes) to afford the title compound (0.24 g, 16%) as ayellow solid. LCMS, [M+H]⁺=284.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 15.91(br. s., 1H), 7.75-7.85 (m, 4H), 3.82 (m, 3H).

4B Methyl 4-(4-bromophenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylate

To a stirred solution of 4A (250 mg, 0.886 mmol) in MeCN (5 mL) wasadded K₂CO₃ (122 mg, 0.886 mmol) and the reaction mixture was allowed tostir at rt for 30 min. CH₃I (0.06 mL, 0.886 mmol) was added and thereaction was stirred at rt under N₂ for 16 h. The reaction mixture wasdiluted with water, extracted with EtOAc (3×15 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was chromatographed (12 g Redisep® SiO₂ column, eluting with 30%EtOAc in n-hexanes) to afford the title compound (200 mg, 70%) as an offwhite solid. ¹H NMR and LCMS showed the presence of a 3:1 ratio of amixture of triazole regioisomers (with the title compound the as majorisomer), which was carried onto the next step without furtherpurification. LC-MS, [M+H]⁺=296.0.

4C (4-(4-Bromophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

To a solution of mixture of 4B (250 mg, 0.844 mmol) in THF (10 mL) undernitrogen was added dropwise LiAlH (0.93 mL of a 1M solution in THF; 0.93mmol) at 0° C. and the reaction mixture was allowed to stir at 0° C. for1 h. The reaction was slowly quenched with water (0.5 mL) and aq. NaOH(0.5 mL of a 10% solution). The reaction mixture was diluted with water(30 mL) and extracted with EtOAc (2×20 mL). The combined organicextracts were washed with brine (25 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was chromatographed (12 g Redisep®SiO₂ column, eluting with 55% EtOAc in n-hexanes) to afford the titlecompound (60 mg, 26%) as an off-white solid. The two regioisomers wereseparated by preparative HPLC (Column: Symmetry C8 (300×19) mm 5 μm;M.Phase A: 0.1% HCO₂H in water; M.Phase B: MeCN, flow rate: 17.0 mL/min;time (min)/% B: 0/45, 35/60;). The desired triazole N-methyl regioisomer4C was isolated as white solid (60 mg 26%) and structurally identifiedby proton NMR NOE studies on the N-methyl group. LC-MS, [M+H]⁺=270.0. ¹HNMR (300 MHz, DMSO-d6) δ ppm 7.80-7.60 (m, 4H), 5.59 (t, J=6.0 Hz, 1H)4.66 (d, J=3 Hz, 2H), 4.08 (s, 3H).

4D (4-(4-Bromophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methylcyclopentylcarbamate

To a stirred solution of cyclopentanecarboxylic acid (63.9 mg, 0.559mmol) and 4C (150 mg, 0.559 mmol) in toluene (4 mL) were added Et₃N(0.10 mL, 0.84 mmol) and Ph₂PON₃ (0.2 mL, 0.671 mmol), and the resultantsolution was stirred at 110° C. for 20 h under N₂. The reaction mixturewas cooled to rt, volatiles were removed in vacuo and the crude productwas chromatographed (12 g Redisep® SiO₂ column, eluting with 38% EtOAcin n-hexanes) to afford the title compound (150 mg, 71%) as an off whitesolid. LC-MS, [M+H]⁺=379.0. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.66 (d, J=8.8Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 5.24 (s, 2H), 4.18 (s, 3H), 3.90-4.00(m, 1H), 2.02-1.90 (m, 2H), 1.50-1.80 (m, 3H), 1.30-1.50 (m, 4H).

4E (4-(4-Bromophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methylcyclopentyl(methyl)carbamate

To a stirred solution of 4D (200 mg, 0.527 mmol) and DMF (4 mL) wasadded NaH (19 mg of a 60% suspension in mineral oil, 0.79 mmol)portionwise at 0° C. and the reaction was stirred at 0° C. for 30 min.Iodomethane (0.049 mL, 0.79 mmol) was added at 0° C. and the reactionwas allowed to warm to rt and stirred at rt for 1 h. The reactionmixture was slowly quenched with aq. HCl (5 mL of a 1.5 N solution),diluted with water (25 mL) and extracted with EtOAc (2×25 mL). Thecombined organic extracts were washed with brine (50 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waschromatographed (12 g Redisep® SiO₂ column, eluting with 40% EtOAc inn-hexanes) to afford the title compound (200 mg, 96%) as a pale yellowoily liquid. LC-MS, [M+H]⁺=395.0.

4F(1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazol-5-yl)methylcyclopentyl(methyl)carbamate

To a stirred solution of 4E (700 mg, 1.78 mmol) andbis(pinacolato)diboron (678 mg, 2.67 mmol) in 1,4-dioxane (7 mL) wasadded KOAc (349 mg, 3.56 mmol) and the reaction mixture was degassedwith N₂ for 5 min. 1,1′-Bis(diphenylphosphino) ferrocenepalladium (II)dichloride-toluene adduct (73 mg, 0.089 mmol) was added and the reactionmixture was stirred at 90° C. for 16 h under N₂. The reaction mixturewas cooled to rt, filtered through a Celite© pad, washed with EtOAc (50mL) and the combined organic filtrates were concentrated in vacuo. Theresidue was chromatographed (24 g Redisep® SiO₂ column, eluting with 75%EtOAc in n-hexanes) to afford the title compound (700 mg, 89%) as a paleyellow oily liquid. LC-MS, [M+H]⁺=441.2.

4G (4-(4-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methylcyclopentyl(methyl)carbamate

To a solution of 4F (700 mg, 1.590 mmol) in THF (20 mL) and water (7 mL)mixture was added sodium perborate monohydrate (317 mg, 3.18 mmol) andthe reaction mixture was stirred at rt for 30 min. The reaction mixturewas diluted with sat'd aq. NH₄Cl (50 mL) and extracted with EtOAc (2×50mL). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was chromatographed (12 gRedisep® SiO₂ column, eluting with 60% EtOAc in n-hexanes) to afford thetitle compound (400 mg, 76%) as a white solid. LC-MS, [M+H]⁺=331.2. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 9.63 (s, 1H), 7.55 (d, J=8.7 Hz, 2H), 6.86(d, J=8.7 Hz, 2H), 5.26 (s, 2H), 4.20-4.50 (m, 1H), 4.09 (s, 3H), 2.67(s, 3H), 1.60-1.80 (m, 4H), 1.40-1.60 (m, 4H).

4H (rac)-trans-Ethyl3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a stirred solution of 4G (300 mg, 0.908 mmol) and di-tert-butylazodicarboxylate (627 mg, 2.72 mmol) and Ph₃P (714 mg, 2.72 mmol) in THF(10 mL) under N₂ was added ethyl 3-hydroxycyclohexanecarboxylate(racemic cis isomer; 313 mg, 1.82 mmol) and the reaction mixture wasstirred at 60° C. for 16 h under N₂, then was cooled to rt andconcentrated in vacuo. The residue was chromatographed (24 g Redisep®SiO₂ column, eluting with 40% EtOAc in n-hexanes) to afford the titlecompound (260 mg, 56%) as a colorless oil. LC-MS, [M+H]⁺=485.2. ¹H NMR(400 MHz, CD₃OD) δ ppm 7.67 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H),5.35 (s, 2H), 4.70-4.80 (m, 1H), 4.18 (s, 3H), 4.12 (q, J=7.2 Hz, 2H),2.70-2.90 (m, 1H), 2.75 (s, 3H), 1.80-2.10 (m, 4H), 1.40-1.80 (m, 13H),1.10-1.30 (t, J=7.2 Hz, 3H).

Example 4(rac)-trans-3-(4-(5-(((Cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylicacid

To a stirred solution of 4H (260 mg, 0.429 mmol) in THF (4 mL) and MeOH(4 mL) was added a solution of LiOH·H₂O (31 mg, 1.29 mmol) in water (4mL) and the reaction mixture was stirred at rt for 16 h. The mixture wasdiluted with water (20 mL) and washed with Et₂O (20 mL) to remove tracesof non-polar impurities. The aqueous layer was neutralized with aq. HCl(2.0 mL of a 1.5N solution) and extracted with 5% MeOH in CHCl₃ (25 mL).The organic layer was washed with brine (25 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The crude product was purified bypreparative HPLC (Column: Symmetry C₈ (300×19) mm 10 μm; M.Phase A: 0.1%HCOOH in water; M.Phase B: MeCN, flow rate: 17.0 mL/min; time (min)/% B:0/30, 20/100;) to afford the title compound (120 mg, 45%) as a whitesolid. LC-MS, [M+H]⁺=457.2. ¹H NMR (400 MHz, CD₃OD) δ 7.66 (d, J=8.40Hz, 2H), 7.09 (d, J=8.80 Hz, 2H), 5.37 (s, 2H), 4.75-4.76 (m, 1H),4.31-4.50 (m, 1H), 4.20 (s, 3H), 2.77-2.81 (m, 4H), 2.07-2.10 (m, 1H),1.82-1.97 (m, 3H), 1.49-1.79 (m, 12H). hLPA1 IC₅₀=18 nM.

Example 5 and Example 6

Individual enantiomers of Example 4 was separated by chiral SFC(Column/dimensions: Chiralpak IC (250×21) mm, 5 μm; % CO₂: 60%; % Cosolvent: 40%(0.25% DEA in MeOH); Total Flow: 60 g/min; Back Pressure:100 bars; Temperature: 25° C.; UV: 250 nm;). Example 5 (37 mg, 18%) wasisolated as a white solid. LC-MS, [M+H]⁺=457.2. OR [α]^(24.8)_(D)=(+)14.0 (c 0.10, MeOH). ¹H NMR (400 MHz, CD₃OD) δ ppm 7.66 (d,J=8.40 Hz, 2H), 7.09 (d, J=8.40 Hz, 2H), 5.37 (s, 2H), 4.75-4.76 (m,1H), 4.31-4.50 (m, 1H), 4.20 (s, 3H), 2.77-2.81 (m, 4H), 2.07-2.10 (m,1H), 1.82-1.97 (m, 3H), 1.49-1.79 (m, 12H). hLPA1 IC₅₀=6 nM. Acute mousein vivo histamine assay: −90% histamine at a 3 mg/kg dose of Example 5.Example 6 (35 mg, 17%) was isolated as a white solid. LC-MS,[M+H]⁺=457.2. OR [α]^(25.2) _(D)=(−)14.0 (c 0.10, MeOH). ¹H NMR (400MHz, CD₃OD) δ 7.66 (d, J=8.40 Hz, 2H), 7.09 (d, J=8.40 Hz, 2H), 5.37 (s,2H), 4.75-4.76 (m, 1H), 4.31-4.50 (m, 1H), 4.20 (s, 3H), 2.77-2.81 (m,4H), 2.07-2.10 (m, 1H), 1.82-1.97 (m, 3H), 1.49-1.79 (m, 12H). hLPA1IC₅₀=1314 nM.

Example 7(1-Methyl-4-(4-(((1S,3S)-3-((methylsulfonyl)carbamoyl)cyclohexyl)oxy)phenyl)-1H-1,2,3-triazol-5-yl)methylcyclopentyl(methyl)carbamate

To a stirred solution of Example 5 (10 mg, 0.022 mmol) and methanesulfonamide (3 mg, 0.033 mmol) in DCM (0.5 mL) and DMF (0.5 mL) mixturewas added 4-dimethylaminopyridine (3.21 mg, 0.026 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.30 mg,0.033 mmol) and the reaction mixture was stirred at rt for 16 h underN₂. The reaction mixture was concentrated in vacuo and the crude productwas purified by preparative HPLC (Column: Sunfire C18 (150×19) mm 5micron; M.Phase A: 0.1% HCO₂H in water; M.Phase B: MeCN, flow rate: 16.0mL/min; time (min)/% B: 0/30, 30/100;) to afford the title compound (4mg, 33%) as a white solid. LC-MS, [M+H]⁺=534.4. ¹H NMR (400 MHz, CD₃OD)δ 7.67 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 5.37 (s, 2H), 4.20 (s,3H), 3.20 (s, 3H), 2.78-2.89 (m, 5H), 1.59-2.10 (m, 17H). hLPA1IC₅₀=3750 nM.

Example 8 & Example 9

8A 4-(4-Methoxyphenyl)-1-methyl-1-H-1,2,3-triazole-5-carbaxaldehyde

To a stirred solution of 4-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazole(35 g, 185 mmol) in THF (860 mL) under N2 was added n-BuLi (111 mL of a2.5 M solution in hexanes, 277 mmol) dropwise at −78° C. and thereaction mixture was stirred at −78° C. for 1 h. DMF (22 mL, 277 mmol)was added at −78° C. and the reaction mixture was allowed to slowly warmto rt and stirred for 2 h at rt. The reaction mixture was cooled to 0°C., then was slowly quenched with sat'd aq. NH₄C₁ and extracted with DCM(3×250 mL). The combined organic extracts were washed with brine (500mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waschromatographed (330 g Redisep© SiO₂ column, eluting with 20% EtOAc inn-hexanes) to afford the title compound (18.0 g, 48%) as a yellow solid.LC-MS, [M+H]⁺=218.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.04 (s, 1H), 7.84(d, J=9.0 Hz, 2H), 7.10 (d, J=9.0 Hz, 2H), 4.31 (s, 3H), 3.84 (s, 3H).

8B4-(4-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde

To a stirred solution of 8A (8.4 g, 38.7 mmol) in DCM (160 mL) was addeddropwise BBr₃ (11 mL, 116 mmol) at 0° C. and the reaction mixture wasstirred at 0° for 1 h. The reaction mixture was quenched carefully withice-cold water and neutralized with 10% aq. NaHCO₃ and extracted withDCM (3×150 mL). The combined organic extracts were washed with brine(250 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was diluted with DCM and the resulting solid that formed wasfiltered and dried in vacuo to afford the title compound (5.7 g, 73%) asa white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.04 (s, 1H), 9.88 (s,1H), 7.71 (d, J=13.0 Hz, 2H), 6.92 (d, J=13.0 Hz, 2H), 4.28 (s, 3H).

8C4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde

To a stirred solution of 8B (1.0 g, 4.92 mmol) and imidazole (0.670 g,9.84 mmol) in DMF (20 mL) was added TBSCl (0.890 g, 5.91 mmol) and thereaction mixture was stirred at rt for 16 h under N₂. Water (100 mL) wasadded to the mixture, which was extracted with EtOAc (2×75 mL). Thecombined organic extracts were washed with brine (150 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waschromatographed (24 g Redisep® SiO₂ column, eluting with 25% EtOAc inn-hexanes) to afford the title compound (1.2 g, 77%) as a white solid.¹H NMR (300 MHz, CDCl₃) δ ppm 10.07 (s, 1H), 7.63 (d, J=8.7 Hz, 2H),6.99 (d, J=8.7 Hz, 2H), 4.36 (s, 3H), 1.01 (s, 9H), 0.24 (s, 6H).

8D(4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

To a 0° C. solution of 8C (1.25 g, 3.94 mmol) in THF (30 mL) was addedNaBH₄ (0.223 g, 5.91 mmol) and the reaction mixture was stirred at 0° C.for 1 h. The reaction mixture was diluted with water (75 mL) andextracted with EtOAc (2×75 mL). The combined organic extracts werewashed with brine (150 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was chromatographed (24 g Redisep® SiO₂ column,eluting with 60% EtOAc in n-hexanes) to afford the title compound (0.7g, 56%) as a white solid. LC-MS, [M+H]⁺=320.3. ¹H NMR (300 MHz, CD₃OD) δppm 7.59 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.77 (s, 2H), 4.15(s, 3H), 1.02 (s, 9H), 0.24 (s, 6H).

8E(4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl(4-nitrophenyl) carbonate

To a stirred solution of 8D (500 mg, 1.565 mmol) and iPr₂NEt (0.50 mL,3.13 mmol) in DCM (10 mL) was added 4-nitrophenyl chloroformate (379 mg,1.88 mmol) at 0° C. and the resultant pale yellow solution was stirredat rt for 16 h under N₂. The reaction mixture was diluted with water (50mL) and extracted with DCM (2×50 mL). The combined organic extracts weredried (Na₂SO₄), filtered and concentrated in vacuo. The crude productwas chromatographed (24 g Redisep® SiO₂ column, eluting with 40% EtOAcin n-hexanes) to afford the title compound (260 mg, 35%) as a whitesolid. LC-MS, [M+H]⁺=485.2. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.30 (d, J=9.0Hz, 2H), 7.64 (d, J=9.0 Hz, 2H), 7.40 (d, J=9.0 Hz, 2H), 6.96 (d, J=8.5Hz, 2H), 5.47 (s, 2H), 4.22 (s, 3H), 1.00 (s, 9H), 0.23 (s, 6H).

8F(4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methylisopentylcarbamate

To a stirred solution of 8E (240 mg, 0.496 mmol) and Et₃N (0.20 mL, 1.49mmol) in THF (10 mL) was added 3-methylbutan-1-amine (86 mg, 0.991 mmol)and the reaction mixture was stirred at rt for 16 h under N₂, then wasconcentrated in vacuo. The crude product was chromatographed (12 gRedisep® SiO₂ column, eluting with 65% EtOAc in n-hexanes) to afford thetitle compound (150 mg, 70%) as a pale yellow liquid. LC-MS,[M+H]⁺=433.4. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.62 (d, J=8.5 Hz, 2H), 6.92(d, J=8.5 Hz, 2H), 5.24 (s, 2H), 4.72 (br. s., 1H), 4.16 (s, 3H),3.27-3.19 (m, 2H), 1.30-1.50 (m, 3H), 0.97-1.00 (s, 9H), 0.91-0.96 (m,6H), 0.23 (s, 6H).

8G (4-(4-Hydroxyphenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methylisopentylcarbamate

To a stirred solution of 8F (150 mg, 0.347 mmol) in THF (6 mL) was addedTBAF (0.52 mL of a 1M solution in THF; 0.52 mmol,) at 0° C. and thereaction mixture was stirred at 0° C. for 30 min. The reaction mixturewas diluted with water (25 mL) and extracted with EtOAc (2×25 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered and concentratedin vacuo. The crude product was chromatographed (12 g Redisep® SiO₂column, eluting with 85% EtOAc in n-hexanes) to afford the titlecompound (90 mg, 82%) as a white solid. LC-MS, [M+H]⁺=319.2. ¹H NMR (400MHz, CD₃OD) δ ppm 7.56 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 5.28(s, 2H), 4.19 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 1.55-1.70 (m, 1H), 1.40(q, J=7.0 Hz, 2H), 0.94 (d, J=6.4 Hz, 6H).

8H (rac)-trans-(Ethyl3-(4-(5-(((isopentylcarbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a stirred solution of 8G (100 mg, 0.314 mmol), di-tert-butylazodicarboxylate (217 mg, 0.942 mmol) and Ph₃P (247 mg, 0.942 mmol) inTHF (10 mL) under N₂ was added ethyl 3-hydroxycyclohexanecarboxylate(racemic cis isomer; 135 mg, 0.785 mmol) and the reaction mixture wasstirred at 60° C. for 16 h under N₂, then was cooled to rt. The reactionmixture was concentrated in vacuo and the crude product waschromatographed (12 g Redisep® SiO₂ column, eluting with 22% EtOAc inn-hexanes) to afford the title compound (90 mg, 60%) as a pale yellowliquid. LC-MS, [M+H]⁺=473.2. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.66 (d,J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 5.29 (s, 2H), 4.75 (br. s., 1H),4.20 (s, 3H), 4.13 (q, J=6.4 Hz, 2H), 3.15 (t, J=7.3 Hz, 2H), 2.80-2.90(m, 1H), 1.60-2.00 (m, 6H), 1.20-1.35 (m, 9H), 0.93 (d, J=6.4 Hz, 6H).

8I (rac)-trans-Ethyl3-(4-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a stirred solution of 8H (90 mg, 0.190 mmol) in DMF (3 mL) under N₂was added NaH (9 mg of a 60% mineral suspension, 0.38 mmol) portionwiseat 0° C. and stirred at 0° C. for 30 min. Iodomethane (0.020 mL, 0.29mmol) was then added and the reaction mixture was allowed to warm to rt& stirred at rt for 1 h. The reaction mixture was diluted with water (30mL) and extracted with EtOAc (2×25 mL). The combined organic extractswere washed with brine (50 mL), dried (Na₂SO₄), and filtered. Thecombined filtrates were concentrated in vacuo. The crude product waspurified by combiflash chromatography (12 g Redisep® SiO₂ column,eluting with 75% EtOAc in n-hexanes) to afford the title compound (60mg, 64%) as a pale yellow liquid. LC-MS, [M+H]⁺=487.2.

Example 8 & Example 9

To a stirred solution of 81 (50 mg, 0.103 mmol) in THF (2 mL) and MeOH(2 mL) mixture was added a solution of LiOH·H₂O (7.0 mg, 0.308 mmol) inwater (2 mL) and the reaction mixture was stirred at rt for 16 h underN₂. The reaction mixture was diluted with water (20 mL) and washed withEt₂O (20 mL) to remove non-polar impurities. The aqueous layer wasneutralized with aq. HCl (2.0 mL of a 1.5 N solution) and extracted withMeOH in CHCl₃ (5% of a 25 mL mixture). The organic layer was washed withbrine (25 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude product was purified by preparative HPLC (Column: Sunfire C18(250×³⁰) mm 5 μm; M.Phase A: 10 mM NH₄OAc in water; M.Phase B: MeCN,flow rate: 15.0 mL/min; time (min)/% B: 0/30, 8/40;) followed byseparation of individual enantiomers by chiral SFC. Example 8 (17 mg,28%) was obtained as a gummy solid. LC-MS, [M+H]⁺=459.2. OR [α]^(25.1)_(D) (+)10.0 (c 0.10, MeOH). ¹H NMR (400 MHz, CD₃OD) δ ppm 7.64-7.70 (m,2H), 7.09 (d, J=8.8 Hz, 2H), 5.36-5.38 (m, 2H), 4.72-4.75 (m, 1H), 4.21(s, 3H), 3.23-3.26 (m, 1H), 2.82-2.90 (m, 4H), 2.06-2.11 (m, 1H),1.92-1.94 (m, 3H), 1.57-1.80 (m, 4H), 1.31-1.45 (m, 4H), 0.82-0.96 (m,6H). hLPA1 IC₅₀=87 nM. Example 9 (14 mg, 24%) was obtained as a gummysolid. LC-MS, [M+H]⁺=459.2. OR [α]^(25.1) _(D)=(−)2.0 (c 0.10, MeOH). ¹HNMR (400 MHz, CD₃OD) δ ppm 7.64-7.70 (m, 2H), 7.09 (d, J=8.4 Hz, 2H),5.36-5.38 (m, 2H), 4.72-4.75 (m, 1H), 4.21 (s, 3H), 3.23-3.26 (m, 1H),2.82-2.90 (m, 4H), 2.06-2.11 (m, 1H), 1.92-1.94 (m, 3H), 1.57-1.80 (m,4H), 1.31-1.45 (m, 4H), 0.82-0.96 (m, 6H). hLPA1 IC₅₀=65 nM.

Example 10(1S,3S)-3-(4-(1-Methyl-5-(((methyl(2-methylpentan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylicacid

10A 4-(4-(Benzyloxy)phenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde

To a stirred mixture of compound 8B (5.5 g, 27.1 mmol) and K₂CO₃ (5.61g, 40.6 mmol) in MeCN (60 mL) was added benzyl bromide (3.54 mL, 29.8mmol) at rt and the reaction mixture was stirred at 70° C. for 3 h underN₂, then was cooled to rt. The reaction mixture was filtered through aCelite© pad, which was washed with DCM (200 mL). The combined filtrateswas concentrated in vacuo to afford the title compound (7.50 g, 80%) asa pale yellow solid, which was carried onto to the next step withoutfurther purification. LC-MS, [M+H]⁺=294.2. ¹H NMR (400 MHz, CDCl₃) δ ppm10.06 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.33-7.49 (m, 5H), 7.12 (d, J=8.8Hz, 2H), 5.15 (s, 2H), 4.37 (s, 3H).

10B (4-(4-(Benzyloxy) phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

To a stirred solution of 10A (8 g, 27.3 mmol) in THF (60 mL) and MeOH(60 mL) was added portionwise NaBH₄ (1.14 g, 30.0 mmol) at 0° C. underN₂ and the reaction mixture was stirred at rt for 1 h. The reactionmixture was diluted with sat'd. aq. NH₄Cl (200 mL) and extracted withEtOAc (2×200 mL). The combined organic extracts were washed with brine(400 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to affordthe title compound (7.0 g, 83%) as a white solid. This crude product wascarried on to the next step without further purification. LC-MS,[M+H]⁺=296.2. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.57 (d, J=9.0 Hz, 2H),7.47-7.33 (m, 5H), 7.04 (d, J=9.0 Hz, 2H), 5.10 (s, 2H), 4.81 (d, J=4.2Hz, 2H), 4.08 (s, 3H), 2.77 (t, J=5.4 Hz, 1H).

10C 4-(4-(Benzyloxy) phenyl)-5-(((tert butyldimethylsilyl) oxy)methyl)-1-methyl-1H-1,2,3-triazole

To a stirred solution of 10B (7 g, 23.70 mmol) and imidazole (4.84 g,71.1 mmol) in DMF (100 mL) was added TBSCl (4.29 g, 28.4 mmol) and thereaction mixture was stirred at rt for 3 h under N₂. The reactionmixture was diluted with water (200 mL) and extracted with EtOAc (2×200mL). The combined organic extracts were washed with brine (400 mL),dried (Na₂SO₄), filtered and concentrated in vacuo to afford the titlecompound (8.0 g, 77%) as a pale yellow solid. This crude product 10c wasused in the next step without further purification. LC-MS, [M+H]⁺=410.2.¹H NMR (300 MHz, CDCl₃) δ ppm 8.03 (s, 1H), 7.61 (d, J=9.0 Hz, 2H),7.33-7.50 (m, 5H), 7.12 (d, J=9.0 Hz, 2H), 5.11 (s, 2H), 4.81 (s, 2H),4.13 (s, 3H), 0.91 (s, 9H), 0.07 (s, 6H).

10D 4-(5-(((tert-Butyldimethylsilyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenol

To a degassed (N₂ was bubbled in for 10 min) solution of 10C (8.0 g,19.53 mmol) in MeOH (150 mL) was added 10% Pd/C (1 g, 0.940 mmol) at rt.The reaction mixture was degassed with H₂ for 5 min. then was stirred atrt under 1 atm of H₂ for 5 h, then the H₂ atmosphere was evacuated andreplaced with N₂. The reaction mixture was filtered through a Celite©pad and washed with MeOH (200 mL). The combined filtrates wasconcentration in vacuo to afford the title compound (5.0 g, 76%) as awhite solid. This crude product 10D was used in the next step withoutfurther purification. LC-MS, [M+H]⁺=320.2.

10E (rac)-trans-Ethyl 3-(4-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a stirred solution of 10D (2.75 g, 8.61 mmol), di-tert-butylazodicarboxylate (7.93 g, 34.4 mmol) and Ph₃P (9.03 g, 34.4 mmol) in THF(80 mL) was added (rac)-cis-ethyl 3-hydroxycyclohexanecarboxylate (5.93g, 34.4 mmol) and the reaction mixture was stirred at 60° C. for 16 hunder N₂, then was cooled to rt. The reaction mixture was concentratedin vacuo. The crude product was chromatographed (120 g Redisep® SiO₂column, eluting with 40% EtOAc in n-hexanes) to afford the titlecompound (2.7 g, 65%) as a colorless liquid. LC-MS, [M+H]⁺=474.2.

10F (1S,3S)-ethyl3-(4-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a stirred solution 10E (200 mg, 0.211 mmol) in THF (6 mL) was addedTBAF (0.317 mL of a 1M solution in THF; 0.317 mmol) at 0° C. and thereaction mixture was stirred at rt under N₂ for 30 min. The reactionmixture was diluted with water (25 mL) and extracted with EtOAc (2×25mL). The combined organic extracts were washed with brine (40 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waschromatographed (12 g Redisep® SiO₂ column, eluting with 75% EtOAc inn-hexanes). The racemic product thus obtained was separated by chiralSFC (Luxcellulose-2 (250×21.5) mm, 5 μm; % CO₂: 70%; % Co-solvent: 30%(0.25% DEA in MeOH); Total Flow: 70 g/min; Back Pressure: 100 bars;Temperature: 35° C.; UV: 230 nm;). The desired S,S enantiomer 10F wasisolated (40 mg, 50%) as an off-white solid: LC-MS, [M+H]⁺=360.2.Optical rotation [α]^(25.2) _(D)=(+)30 (c 0.10, MeOH). ¹H NMR (400 MHz,CD₃OD) δ ppm 7.63 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 4.79 (s,2H), 4.72-4.76 (m, 1H), 4.18 (s, 3H), 4.16 (q, J=7.0 Hz, 2H), 2.80-2.88(m, 1H), 2.03-2.11 (m, 1H), 1.88-1.98 (m, 3H), 1.57-1.82 (m, 4H),1.25-1.30 (m, 3H).

10G (1S,3S)-Ethyl-3-(4-(1-methyl-5-((((2-methylpentan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a solution of 10F (50 mg, 0.14 mmol), 2,2-dimethylpentanoic acid (18mg, 0.139 mmol) and Et₃N (0.029 mL, 0.21 mmol) in toluene (3 mL) wasadded Ph₂PON₃ (0.036 mL, 0.167 mmol) and the resultant pale yellowsolution was stirred at 110° C. for 16 h under N₂, then was cooled tort. The reaction mixture was concentrated in vacuo and the crude productwas chromatographed (12 g Redisep® SiO₂ column, eluting with 50% EtOAcin n-hexanes) to afford the title compound (40 mg, 50%) as a whitesolid. LC-MS, [M+H]⁺=487.2. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.65 (d, J=9.2Hz, 2H), 7.08 (d, J=9.2 Hz, 2H), 5.24 (s, 2H), 4.75 (br. s., 1H), 4.19(s, 3H), 4.16 (q, J=7.2 Hz, 2H), 3.15 (s, 1H), 2.86 (d, J=11.0 Hz, 2H),2.07 (br. s., 1H), 1.89-1.99 (m, 3H), 1.60-1.80 (m, 4H), 1.20-1.40 (m,8H), 0.95-0.88 (m, 6H).

10H (1S,3S)-Ethyl3-(4-(1-methyl-5-(((methyl(2-methylpentan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a stirred solution of 10G (40.0 mg, 0.082 mmol) in DMF (3 mL) underN₂ was added NaH (4 mg of a 60% mineral suspension, 0.16 mmol)portionwise at 0° C. and stirred for 30 min. Iodomethane (7.71 μl, 0.123mmol) was then added and the reaction mixture was stirred at rt for 1 h,then was diluted with water (20 mL). The mixture was extracted withEtOAc (2×20 mL) and the combined organic extracts were washed with brine(25 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct was chromatographed (12 g Redisep® SiO₂ column, eluting with 75%EtOAc in n-hexanes) to afford the title compound (30 mg, 73%) as a paleyellow liquid. LC-MS, [M+H]⁺=501.2.

Example 10

To a stirred solution of 10H (30.0 mg, 0.060 mmol) in THF (1.5 mL) andMeOH (1.5 mL) was added a solution of LiOH·H₂O (4.3 mg, 0.18 mmol) inwater (1.5 mL) and the reaction mixture was stirred at rt for 16 h underN₂. The reaction mixture was diluted with water (20 mL) and washed withEt₂O (20 mL) to remove traces of nonpolar impurities. The aqueous layerwas neutralized with aq. HCl (2.0 mL of a 1.5 N solution) and extractedwith 5% MeOH in CHCl₃ (25 mL). The organic layer was washed with brine(25 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidual crude product was purified by preparative HPLC (KinetexBiphenyl 100A (2500×^(21.1)) mm 5 μm; Mobile Phase A: 0.1% HCO₂H inwater; Mobile Phase B: MeCN, flow rate: 18.0 mL/min; time (min)/% B:0/40, 32/75, 35/95;) to afford the title compound (8 mg, 28%) as a whitesolid. LC-MS, [M+H]⁺=473.2. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.63 (d,J=8.80 Hz, 2H), 7.07 (d, J=8.80 Hz, 2H), 5.31 (s, 2H), 4.83-4.89 (m,1H), 4.18 (s, 3H), 2.85 (s, 3H), 2.72-2.76 (m, 1H), 2.06-2.10 (m, 1H),1.82-1.95 (m, 3H), 1.40-1.77 (m, 6H), 1.29 (s, 6H), 1.11-1.24 (m, 2H),0.08-0.84 (m, 3H). hLPA1 IC₅₀=23 nM.

Example 11(rac)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylicacid

Example 11 was prepared according to the procedure of Example 2 by usingIntermediate 1 instead of (1S,3R)-isopropyl3-hydroxy-cyclohexanecarboxylate in the procedure (Mitsunobu reaction)to synthesize Example 2F. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=8.8 Hz,1H), 8.00-7.89 (m, 1H), 5.53-5.32 (m, 2H), 5.00 (br. s., 1H), 4.21 (d,J=2.4 Hz, 3H), 3.32 (dd, J=10.8, 7.5 Hz, 2H), 2.92 (d, J=13.6 Hz, 3H),2.75 (d, J=2.6 Hz, 3H), 2.55 (dt, J=15.5, 7.8 Hz, 1H), 2.47-2.27 (m,1H), 2.24-1.77 (m, 10H), 1.76-1.58 (m, 3H); ¹⁹F NMR (377 MHz, CDCl₃) δ−76.0 (s, F from TFA), −154.4 (s, 1F). LC-MS, [M+H]⁺=490.4. hLPA1IC₅₀=12 nM.

Example 12(1S,3S)-3-(4-(5-(1-(((cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1-carboxylicacid (diastereomeric mixture)

12A1-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-methyl-1H-1,2,3-triazol-5-yl)ethan-1-ol

To a −40° C. solution of 8C (279 mg, 0.879 mmol) in THF (18 mL) wasadded CH₃MgBr (439 μL of a 3 M solution in THF, 1.32 mmol). The reactionmixture was allowed to warm to rt and stirred at rt for 1 h. Water (15mL) was added and the mixture was extracted with EtOAc (2×30 mL). Thecombined organic extracts were concentrated in vacuo and chromatographed(SiO₂; continuous gradient from 0% to 100% EtOAc in Hexanes, 20 min) togive 12A (230 mg, 78%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d,J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.33 (dd, J=6.8, 3.5 Hz, 1H),4.23 (s, 3H), 1.96 (d, J=3.3 Hz, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.00 (s,9H), 0.22 (s, 6H)

Example 12 was prepared according to the procedure for the synthesis ofExample 8 by using 12A instead of 8D. ¹H NMR (500 MHz, DMSO-d₆) δ 7.57(br. s., 2H), 7.06 (d, J=6.6 Hz, 2H), 6.19-5.87 (m, 1H), 4.69 (br. s.,1H), 4.13 (d, J=5.6 Hz, 3H), 3.21-3.09 (m, 2H), 2.76 (d, J=15.7 Hz, 3H),2.45-2.37 (m, 1H), 2.01-1.45 (m, 18H). LC-MS, [M+H]⁺=471.0. hLPA1IC₅₀=384 nM.

Example 133-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylicacid (single enantiomer)

Example 13 was subjected to chiral SFC (Column: Chiralpak IC, 21×250 mm,5 micron Mobile Phase: 40% MeOH/60% CO₂ Flow Conditions: 45 mL/min, 150Bar, 40° C. Detector Wavelength: 254 nm Injection Details: 0.5 mL of 5mg/mL solution in MeOH) to afford Example 13. ¹H NMR (500 MHz, CDCl₃) δ8.11-7.96 (m, 1H), 7.29 (d, J=8.5 Hz, 1H), 5.75 (d, J=9.6 Hz, 2H), 4.79(d, J=3.3 Hz, 1H), 4.15 (d, J=7.7 Hz, 3H), 3.38-3.11 (m, 2H), 2.93-2.75(m, 3H), 2.65-2.51 (m, 1H), 2.25 (br. s., 1H), 2.10-1.47 (m, 7H). LC-MS,[M+H]⁺=490.4. hLPA1 IC₅₀=95 nM.

Example 14(4-(5-(((1S,3S)-3-carbamoylcyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate

To a solution of Example 2 (100 mg, 0.21 mmol) and DMF (0.8 μL, 11 μmol)in CH₂Cl₂ (2 mL) was slowly added oxalyl chloride (0.21 mL, 0.42 mmol);the mixture was stirred at rt for 30 min. The mixture was concentratedin vacuo to give the acid chloride. To the acid chloride in CH₂Cl₂ (1.0mL) was added ammonia (6.36 mL of a 0.5 N solution in dioxane, 3.18mmol). The mixture was stirred at rt for 30 min, then was concentratedin vacuo. The residual crude product was chromatographed (SiO₂; 12 g;A=DCM, B=EtOAc; 12 min gradient from 0% B to 100% B; flow rate=30mL/min) to afford the title compound (77 mg, 0.17 mmol, 89% yield) as awhite solid. LCMS, [M+H]⁺=471.2. ¹H NMR (500 MHz, DMSO-d₆) [rotamer,ratio 53:47] [major rotamer-underline; minor rotamer—Italic]: 6 ppm 7.81(d, J=8.5 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.35 (s, 1H), 6.72 (s, 1H),5.62 (s, 2H), 5.59 (s, 2H), 4.81 (br-s, 1H), 4.08 (br-s, 3H), 3.21(br-s, 2H), 3.08 (br-s, 2H), 2.77-2.65 (m, 4H), 2.55 (s, 3H), 2.43 (s,3H), 2.37-1.36 (m, 12H). HPLC-6: RT=1.36 min, purity=98%. hLPA1 IC₅₀=824nM.

Example 15(4-(5-(((1S,3S)-3-cyanocyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate

A mixture of Example 14 (90 mg, 0.19 mmol) and Burgess reagent (137 mg,0.57 mmol) in DCM (1 mL) and THF (1 mL) was stirred at rt for 48 h, thenwas concentrated in vacuo. The residue was chromatographed (SiO₂; 12 g;A=DCM, B=EtOAc; 12 min gradient from 0% B to 100% B; flow rate=30mL/min) to afford the title compound (85 mg, 0.18 mmol, 95% yield) as awhite solid. LCMS, [M+H]⁺=453.0. ¹H NMR (500 MHz, DMSO-d₆) [rotamer,ratio 53:47] [major rotamer—underline; minor rotamer-Italic]: δ ppm 7.83(d, J=8.5 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 5.62 (s, 2H), 5.58 (s, 2H),4.71 (s, 1H), 4.08 (br-s, 3H), 3.22 (br-s, 2H), 3.08 (br-s, 2H),2.77-2.65 (m, 4H), 2.55 (s, 3H), 2.40 (s, 3H), 2.34-1.34 (m, 12H).HPLC-6: RT=1.68 min, purity=97%. hLPA1 IC₅₀=3750 nM.

Example 16(4-(5-(((1S,3S)-3-(1H-tetrazol-5-yl)cyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate

A mixture of Example 15 (69 mg, 0.15 mmol), TEA (0.32 mL, 2.3 mmol),NaN₃ (149 mg, 2.3 mmol) and HOAc (0.13 mL, 2.3 mmol) in toluene (1.0 mL)in a sealed tube was stirred at 100° C. for 18 h, then was cooled to rt.The mixture was diluted with EtOAc (5 mL), quenched with sat'd. aq.NaHCO₃ (3 mL). The mixture was extracted with EtOAc (5×5 mL). Thecombined organic extracts were dried (MgSO₄), filtered, and concentratedin vacuo. The crude material was purified by preparative LC/MS using thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 MeCN: water with 10 mM NH₄OAc; Mobile Phase B: 95:5MeCN: water with 10 mM NH₄OAc; Gradient: 10-60% B over 20 min, then a5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (54 mg, 70% yield) as a white solid. LCMS,[M+H]⁺=496.0. ¹H NMR (500 MHz, DMSO-d₆) [rotamer, ratio 53:47] [majorrotamer—underline; minor rotamer—Italic]: δ ppm 7.82 (d, J=8.5 Hz, 1H),7.49 (d, J=8.6 Hz, 1H), 5.61 (s, 2H), 5.57 (s, 2H), 4.88 (s, 1H), 4.07(br-s, 3H), 3.37 (m, 1H), 3.20 (br-s, 2H), 3.06 (br-s, 2H), 2.76-2.65(m, 3H), 2.54 (s, 3H), 2.44 (s, 3H), 2.37-1.33 (m, 12H). HPLC-6: RT=1.50min, purity=96%. hLPA1 IC₅₀=22 nM.

Example 17(1-methyl-4-(6-methyl-5-(((1S,3S)-3-((methylsulfonyl)carbamoyl)cyclohexyl)oxy)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate

To a clear solution of Example 2 (15 mg, 0.032 mmol) andmethanesulfonamide (5 mg, 0.048 mmol) and DMAP (6 mg, 0.048 mmol) in DMF(0.2 mL) and DCM (1 mL) was added EDC (9.4 mg, 0.048 mmol). The mixturewas stirred at rt for 62 h, then was diluted with water (2 mL) and DCM(5 mL). The organic layer was washed with brine (5 mL), dried (MgSO₄)and concentrated in vacuo to afford a white solid, which was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5 m particles; Mobile Phase A: 5:95 MeCN: water with 10mM NH₄OAc; Mobile Phase B: 95:5 MeCN: water with 10 mM NH₄OAc; Gradient:20-70% B over 20 min, then a 3-min hold at 100% B; Flow: 20 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (14 mg, 78% yield)as a white solid. LCMS, [M+H]⁺=549.3. ¹H NMR (500 MHz, DMSO-d₆)[rotamer, ratio 53:47] [major—underlined; minor—Italic]: δ ppm 7.82 (d,J=8.6 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 5.62 (s, 2H), 5.58 (s, 2H), 4.85(s, 1H), 4.08 (br-s, 3H), 3.60 (m, 1H), 3.24-3.08 (m, 2H), 2.79-2.67 (m,4H), 2.54 (s, 6H), 2.44 (s, 3H), 2.35-1.35 (m, 12H). HPLC-6: RT=1.56min, purity=97%. hLPA1 IC₅₀=352 nM.

TABLE 1 Analytical & Biology Example Structure & Name Data Method 18

LCMS, [M + H]⁺ = 458.3. ¹H NMR (500 MHz, CD₃CN) δ 8.26 (dd, J = 3.0, 0.6Hz, 1H), 8.00- 7.96 (m, 1H), 7.38 (dd, J = 8.8 2.8 Hz, 1H), 5.58 (s,2H), 4.70 (br. s., 1H), 4.03 (s, 3H), 2.79-2.69 (m, 1H), 2.64 (br. s.,3H), 2.01-1.93 (m, 2H), 1.84- 1.73 (m, 3H), 1.71- 1.49 (m, 8H),1.48-1.36 (m, 4H) hLPA1 IC₅₀ = 21 nM. Example 2 (rac)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 19

LCMS, [M + H]⁺ = 508.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.38- 6.97 (m, 5H), 5.68 (br s, 2H),5.36 (br s, 1H), 5.10 (br s, 1H), 4.76 (br s, 1H), 4.14-3.98 (m, 2H),3.69 (br d, J = 7.7 Hz, 1H), 2.63-2.55 (m, 2H), 2.49-2.44 (m, 1H), 2.38(br s, 3H), 1.99 (br d, J = 14.4 Hz, 1H), 1.87- 1.70 (m, 3H), 1.67-1.28(m, 7H) hLPA1 IC₅₀ = 17 nM Example 3 (1S,3S)-342-methyl-6-(1-methyl-5-(((methyl((R)-1- phenylethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 20

LCMS, [M + H]⁺ = 486.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.3Hz, 1H), 7.48 (br d, J = 8.6 Hz, 1H), 5.85- 5.43 (m, 2H), 4.77 (br s,1H), 4.28-3.96 (m, 3H), 2.55 (s, 6H), 2.42 (br d, J = 8.6 Hz, 3H), 1.97(br s, 1H), 1.87-1.17 (m, 13H), 1.00-0.75 (m, 3H) hLPA1 IC₅₀ = 28 nM.Example 1 (1S,3S)-3-((6-(5-((((1- cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) 21

LCMS, [M + H]⁺ = 494.4 ¹H NMR (500 MHz, DMSO-d₆) δ 8.43-8.29 (m, 1H),8.07-7.94 (m, 1H), 7.66-7.51 (m, 1H), 7.42-7.04 (m, 5H), 5.78- 5.57 (m,2H), 5.45- 5.03 (m, 1H), 4.87-4.73 (m, 1H), 4.22-3.95 (m, 3H), 2.74-2.63(m, 1H), 2.60-2.56 (m, 3H), 2.00- 1.91 (m, 1H), 1.90- 1.71 (m, 3H),1.70-1.59 (m, 2H), 1.57-1.33 (m, 5H) hLPA1 IC₅₀ = 21 nM. Example 1(1S,3S)-3-((6-(1-methyl-5- (((methyl((R)- 1-phenylethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 22

LCMS, [M + H]⁺ = 480.1. ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (br. s., 1H),8.01 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 7.0 Hz, 1H), 7.41-6.96 (m, 5H),5.77-5.56 (m, 2H), 4.78 (br. s., 1H), 4.50-4.25 (m, 2H), 4.18-3.91 (m,3H), 3.50 (br. s., 1H), 2.84-2.62 (m, 3H), 2.02- 1.74 (m, 4H), 1.71-1.45 (m, 4H) hLPA1 IC₅₀ = 18 nM. Example 1 (1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 23

LCMS, [M + H]⁺ = 458.3 ¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (br. s., 1H),7.99 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 5.62 (d, J = 19.2Hz, 2H), 4.77 (br. s., 1H), 4.11 (d, J = 6.1 Hz, 3H), 3.56-3.41 (m, 1H),3.28- 3.04 (m, 2H), 2.80- 2.67 (m, 3H), 2.02-1.40 (m, 15H) hLPA1 IC₅₀ =12 nM. Example 1 (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 24

LCMS, [M + H]⁺ = 460.3 ¹H NMR (500 MHz, DMSO-d₆) δ 8.44-8.29 (m, 1H),8.07-7.95 (m, 1H), 7.55 (br d, J = 7.3 Hz, 1H), 5.73-5.52 (m, 2H), 4.78(br s, 1H), 4.20- 4.03 (m, 3H), 2.70- 2.59 (m, 2H), 1.99-1.71 (m, 6H),1.68-1.49 (m, 4H), 1.43-1.09 (m, 4H), 1.06-0.78 (m, 6H), 0.82- 0.58 (m,1H) hLPA1 IC₅₀ = 47 nM. Example 1 (1S,3S)-3-((6-(1-methyl-5-(((methyl(pentan-2- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid(diastereomeric mixture) 25

LCMS, [M + H]⁺ = 458.3 ¹H NMR (400 MHz, CD₃CN) δ 8.24 (br. s., 1H), 8.12(d, J = 8.1 Hz, 1H), 7.93 (dd, J = 9.1, 2.5 Hz, 1H), 5.17 (br. s., 2H),4.80-4.59 (m, 1H), 3.97 (d, J = 15.8 Hz, 3H), 3.31- 3.07 (m, 1H), 2.72-2.54 (m, 4H), 2.02-1.76 (m, 3H), 1.70-1.33 (m, 5H), 1.09-0.87 (m, 3H),0.84-0.65 (m, 1H), 0.46- 0.13 (m, 4H) hLPA1 IC₅₀ = 20 nM. Example 3(1S,3S)-3-((6-(5-(((((R)-1- cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 26

LCMS, [M + H]⁺ = 497.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.73-7.41 (m, 2H),7.38-6.98 (m, 6H), 5.43-5.26 (m, 2H), 4.72 (br. s., 1H), 4.39 (d, J =8.9 Hz, 2H), 4.20- 3.95 (m, 3H), 3.67-3.42 (m, 3H), 2.69-2.60 (m, 1H),1.96 (br. s., 1H), 1.82 (t, J = 11.1 Hz, 3H), 1.69-1.45 (m, 5H) hLPA1IC₅₀ = 34 nM. Example 1 (1S,3S)-3-(4-(5- (((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-fluorophenoxy)cyclohexane-1-carboxylic acid 27

LCMS, [M + H]⁺ = 475.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.70-7.48 (m, 2H),7.33 (t, J = 8.7 Hz, 1H), 5.32 (d, J = 7.9 Hz, 2H), 4.75 (br. s., 1H),4.12 (br. s., 3H), 3.65- 3.44 (m, 4H), 3.26-3.07 (m, 2H), 2.69-2.60 (m,1H), 2.01-1.41 (m, 14H) hLPA1 IC₅₀ = 14 nM. Example 1 (1S,3S)-3-(4-(5-((((cyclobutylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- fluorophenoxy)cyclohexane-1- carboxylic acid 28

LCMS, [M + H]⁺ = 477.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.70-7.43 (m, 2H),7.32 (br t, J = 8.5 Hz, 1H), 5.33 (br s, 2H), 4.75 (br s, 1H), 4.12 (s,3H), 3.90 (br s, 1H), 3.52 (br d, J = 16.5 Hz, 2H), 2.71-2.59 (m, 2H),1.97 (br s, 1H), 1.88-1.76 (m, 3H), 1.71-1.45 (m, 4H), 1.43-1.18 (m,2H), 1.14- 0.91 (m, 5H), 0.82 (br t, J = 6.9 Hz, 2H), 0.76- 0.66 (m, 1H)hLPA1 IC₅₀ = 25 nM. Example 1 (1S,3S)-3-(2-fluoro-4-(1-methyl-5-(((methyl(pentan-2- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (diastereomericmixture) 29

LCMS, [M + H]⁺ = 472.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.69 (d, J = 8.2 Hz,1H), 7.33 (d, J = 8.2 Hz, 1H), 5.74- 5.34 (m, 2H), 4.64 (br. s., 1H),3.95 (s, 3H), 3.27 (br. s., 1H), 2.67-2.44 (m, 4H), 2.27 (s, 3H), 1.88(d, J = 14.0 Hz, 1H), 1.79-1.59 (m, 3H), 1.56- 1.27 (m, 4H), 1.05- 0.63(m, 4H), 0.44-−0.39 (m, 4H) hLPA1 IC₅₀ = 41 nM. Example 3 (1S,3S)-3-((6-(5-(((((R)-1- cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 30

LCMS, [M + H]⁺ = 494.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.86 (d, J = 8.5 Hz,1H), 7.49 (d, J = 8.5 Hz, 1H), 7.39- 6.97 (m, 5H), 5.79-5.63 (m, 2H),4.79 (br. s., 1H), 4.49-4.26 (m, 2H), 4.17- 3.91 (m, 3H), 2.86- 2.69 (m,3H), 2.68-2.59 (m, 1H), 2.41 (d, J = 14.3 Hz, 3H), 2.07-1.98 (m, 1H),1.92-1.74 (m, 3H), 1.71-1.45 (m, 4H) hLPA1 IC₅₀ = 16 nM. Example 1(1S,3S)-3-((6-(5- (((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 31

LCMS, [M + H]⁺ = 474.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.2 Hz,1H), 7.48 (d, J = 7.0 Hz, 1H), 5.66 (br. s., 2H), 4.79 (br. s., 1H),4.10 (s, 4H), 2.63 (br. s., 3H), 2.42 (s, 3H), 2.10- 1.97 (m, 1H),1.91-1.71 (m, 4H), 1.67-1.10 (m, 6H), 1.06-0.80 (m, 4H), 0.64 (br. s.,2H) hLPA1 IC₅₀ = 36 nM. Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pentan-2- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid(diastereomeric mixture) 32

LCMS, [M + H]⁺ = 460.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J = 8.5 Hz,1H), 7.48 (d, J = 8.5 Hz, 1H), 5.64 (d, J = 15.9 Hz, 2H), 4.79 (br. s.,1H), 4.10 (s, 3H), 3.53- 3.32 (m, 2H), 3.23- 3.02 (m, 1H), 2.85-2.69 (m,3H), 2.42 (s, 3H), 1.81 (br. s., 3H), 1.63 (d, J = 9.8 Hz, 6H), 1.31-0.96 (m, 3H), 0.66 (br. s., 3H) hLPA1 IC₅₀ = 10 nM. Example 1(1S,3S)-3-((6-(5- (((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 33

LCMS, [M + H]⁺ = 472.4 ¹H NMR (400 MHz, CD₃CN) δ 7.96-7.79 (m, 1H), 7.35(d, J = 8.8 Hz, 1H), 5.67 (br s, 2H), 4.86-4.62 (m, 1H), 4.19- 3.97 (m,4H), 3.39- 3.01 (m, 2H), 2.88-2.63 (m, 4H), 2.60-2.29 (m, 4H), 2.18-2.04(m, 1H), 1.91-1.44 (m, 12H), 1.29-1.15 (m, 1H) hLPA1 IC₅₀ = 7 nM.Example 1 (1S,3S)-3-((6-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 34

LCMS, [M + H]⁺ = 474.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J = 8.5 Hz,1H), 7.48 (d, J = 8.5 Hz, 1H), 5.63 (d, J = 15.3 Hz, 2H), 4.79 (br. s.,1H), 4.10 (br. s., 3H), 3.44 (br. s., 1H), 3.22 (br. s., 1H), 3.06 (br.s., 1H), 2.84-2.69 (m, 3H), 2.63 (t, J = 10.4 Hz, 1H), 2.42 (s, 3H),2.09-1.97 (m, 2H), 1.92-1.70 (m, 2H), 1.70-1.42 (m, 4H), 1.40- 1.19 (m,2H), 1.14 (br. s., 1H), 0.88 (br. s., 3H), 0.62 (d, J = 4.6 Hz, 3H)Example 1 hLPA1 IC₅₀ = 16 nM. (1S,3S)-3-((6-(5-(((isopentyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 35

LCMS, [M + H]⁺ = 528.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J = 8. Hz,1H), 7.49 (d, J = 8.5 Hz, 1H), 7.44- 6.99 (m, 4H), 5.83-5.59 (m, 2H),4.79 (br. s., 1H), 4.49-4.25 (m, 2H), 4.18- 3.93 (m, 3H), 2.86- 2.68 (m,3H), 2.67-2.60 (m, 1H), 2.45-2.29 (m, 3H), 2.03 (d, J = 13.7 Hz, 1H),1.94-1.73 (m, 3H), 1.71-1.44 (m, 4H) hLPA1 IC₅₀ = 284 nM. Example 1(1S,3S)-3-((6-(5-((((4- chlorobenzyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 36

LCMS, [M + H]⁺ = 471.3 ¹H NMR (400 MHz, CD₃CN) δ 7.48-7.31 (m, 2H), 6.87(d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 4.62 (br. s., 1H), 3.95 (s, 3H),2.70-2.56 (m, 4H), 2.13 (s, 3H), 2.02-1.92 (m, 1H), 1.65-1.33 (m, 8H),0.99 (br. s., 3H), 0.83-0.68 (m, 1H), 0.37 br. s., 1H), 0.26-−0.22 (m,3H) hLPA1 IC₅₀ = 6 nM. Example 3 (1S,3S)-3-(4-(5-(((((R)-1-cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- methylphenoxy)cyclohexane-1- carboxylic acid 37

LCMS, [M + H]⁺ = 471.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.66-7.42 (m, 2H),7.06 (d, J = 8.5 Hz, 1H), 5.28 (br. s., 2H), 4.74 (br. s., 1H), 4.10(br. s., 3H), 3.48-3.34 (m, 2H), 2.76 (br. s., 2H), 2.65-2.58 (m, 1H),2.22 (br. s., 3H), 2.02-1.40 (m, 15H) hLPA1 IC₅₀ = 14 nM. Example 1(1S,3S)-3-(4-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylphenoxy)cyclohexane-1- carboxylic acid 38

LCMS, [M + H]⁺ = 493.0 ¹H NMR (500 MHz, DMSO-d₆) δ 7.65-7.39 (m, 2H),7.37-6.94 (m, 7H), 5.32 (d, J = 19.5 Hz, 2H), 4.72 (br. s., 1H), 4.39(d, J = 13.4 Hz, 2H), 4.18-3.95 (m, 3H), 2.89- 2.70 (m, 3H), 2.62 (br.s., 1H), 2.24-2.10 (m, 3H), 2.00 (d, J = 11.9 Hz, 1H), 1.90-1.71 (m,3H), 1.69-1.39 (m, 4H) hLPA1 IC₅₀ = 32 nM. Example 1 (1S,3S)-3-(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazol-4-yl)-2-methylphenoxy)cyclohexane-1- carboxylic acid 39

LCMS, [M + H]⁺ = 473.3. ¹H NMR (500 MHz, DMSO-d₆) δ 7.62-7.42 (m, 2H),7.05 (d, J = 8.5 Hz, 1H), 5.27 (br. s., 2H), 4.74 (br. s., 1H), 4.09 (s,3H), 3.43 (br. s., 2H), 2.68-2.54 (m, 4H), 2.21 (s, 3H), 2.01 (d, J =13.7 Hz, 1H), 1.88-1.71 (m, 3H), 1.69-1.18 (m, 6H), 1.16-0.66 (m, 6H)hLPA1 IC₅₀ = 23 nM. Example 1 (1S,3S)-3-(2-methyl-4-(1-methyl-5-(((methyl(pentan-2- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (diastereomericmixture) 40

LCMS, [M + H]⁺ = 459.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.52 (d, J = 13.1 Hz,2H), 7.05 (d, J = 7.6 Hz, 1H), 5.27 (d, J = 5.5 Hz, 2H), 4.74 (br. s.,1H), 4.09 (s, 3H), 3.23- 3.04 (m, 2H), 2.77 (d, J = 6.4 Hz, 3H), 2.61(br. s., 1H), 2.22 (s, 3H), 2.00 (d, J = 12.8 Hz, 1H), 1.90- 1.69 (m,3H), 1.67- 1.04 (m, 8H), 0.91-0.61 (m, 3H) hLPA1 IC₅₀ = 28 nM. Example 1(1S,3S)-3-(4-(5- (((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-methylphenoxy)cyclohexane-1-carboxylic acid 41

LCMS, [M + H]⁺ = 471.3, ¹H NMR (500 MHz, DMSO-d₆) δ 7.60-7.44 (m, 2H),7.04 (d, J = 8.5 Hz, 1H), 5.28 (s, 2H), 4.74 (br. s., 1H), 4.09 (s, 3H),3.42 (br. s., 1H), 2.72-2.58 (m, 4H), 2.27- 2.17 (m, 3H), 2.01 (d, J =13.4 Hz, 1H), 1.89- 1.71 (m, 3H), 1.69-1.32 (m, 12H) hLPA1 IC₅₀ = 14 nM.Example 1 (1S,3S)-3-(4-(5- (((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylphenoxy)cyclohexane-1-carboxylic acid 42

LCMS, [M + H]⁺ = 474.3. ¹H NMR (500 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.90(s, 1H), 5.62 (d, J = 18.0 Hz, 2H), 4.88 (br. s., 1H), 4.10 (br. s.,3H), 3.26-3.04 (m, 2H), 2.76 (d, J = 17.7 Hz, 3H), 2.65 (br. s., 1H),2.28 (s, 3H), 2.03 (d, J = 12.8 Hz, 1H), 1.93-1.77 (m, 3H), 1.70-1.06(m, 7H), 0.88 (d, J = 4.6 Hz, 3H), 0.67 (d, J = 5.2 Hz, 3H) hLPA1 IC₅₀ =3750 nM. Example 1 (1S,3S)-3-((6-(5- (((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-4-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 43

LCMS, [M + H]⁺ = 446.3. ¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (d, J = 2.4 Hz,1H), 8.00 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 5.62 (d, J =18.0 Hz, 2H), 4.79 (br. s., 1H), 4.11 (s, 3H), 3.24- 3.04 (m, 2H), 2.82-2.62 (m, 4H), 1.98 (d, J = 14.0 Hz, 1H), 1.89- 1.73 (m, 3H), 1.72-1.37(m, 5H), 1.26 (br. s., 2H), 1.05 (br. s., 1H), 0.88 (br. s., 2H), 0.69(br. s., 2H) hLPA1 IC₅₀ = 7 nM. Example 1 (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 44

LCMS, [M + H]⁺ = 475.2 ¹H NM (500 MHz, DMSO-d₆) δ 7.61 (d, J = 12.2 Hz,1H), 7.53 (d, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 5.34 (s, 2H),4.75 (br. s., 1H), 4.13 (s, 3H), 3.46-3.30 (m, 1H), 2.73-2.59 (m, 4H),2.01-1.30 (m, 16H) hLPA1 IC₅₀ = 6 nM. Example 1 (1S,3S)-3-(4-(5-(((cyclopentyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-fluorophenoxy)cyclohexane- 1-carboxylic acid 45

LCMS, [M + H]⁺ = 475.4 ¹H NMR (500 MHz, DMSO-d₆) δ 7.61-7.39 (m, 2H),7.30-7.19 (m, 1H), 5.23 (s, 2H), 4.66 (br. s., 1H), 4.02 (s, 3H), 3.29(br. s., 1H), 2.65 (br. s., 3H), 2.60-2.52 (m, 1H), 1.94-1.85 (m, 1H),1.73 (d, J = 11.0 Hz, 3H), 1.56 (d, J = 8.5 Hz, 2H), 1.44 (br. s., 2H),0.98 (d, J = 16.2 Hz, 4H), 0.51-−0.31 0.31 (m, 4H) hLPA1 IC₅₀ = 20 nM.Example 1 (1S,3S)-3-(4-(5-((((1- cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-fluorophenoxy)cyclohexane-1- carboxylic acid (diastereomeric mixture) 46

LCMS, [M + H]⁺ = 463.0 ¹H NMR (500 MHz, DMSO-d₆) δ 7.69-7.45 (m, 2H),7.35 (br. s., 1H), 5.34 (br. s., 2H), 4.75 (br. s., 1H), 4.13 (s, 3H),3.23- 3.06 (m, 2H), 2.78 (d, J = 8.9 Hz, 3H), 2.63 (br. s., 1H),1.99-1.04 (m, 12H), 0.93-0.70 (m, 3H) hLPA1 IC₅₀ = 6 nM. Example 1(1S,3S)-3-(4-(5- (((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-fluorophenoxy)cyclohexane-1-carboxylic acid 47

LCMS, [M + H]⁺ = 477.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.77-7.43 (m, 2H),7.33 (br. s., 1H), 5.34 (d, J = 7.9 Hz, 2H), 4.75 (br. s., 1H), 4.13(br. s., 3H), 3.23-3.06 (m, 2H), 2.78 (d, J = 14.6 Hz, 3H), 2.67 (br.s., 1H), 1.98 (br. s., 1H), 1.89- 1.11 (m, 10H), 0.96- 0.65 (m, 6H)hLPA1 IC₅₀ = 3 nM. Example 1 (1S,3S)-3-(2-fluoro-4-(5-(((isopentyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid 48

LCMS, [M + H]⁺ = 471.3 ¹H NMR (400 MHz, CDCl₃) δ 7.73 (br s, 2H), 7.04(br d, J = 7.5 Hz, 2H), 5.32 (s, 2H), 4.72 (br s, 1H), 4.19 (br s, 3H),2.94 (br d, J = 3.1 Hz, 1H), 2.67 (s, 3H), 2.47-1.58 (m, 16H), 1.02 (brs, 3H) hLPA1 IC₅₀ = 8 nM. Example 1 (1S,3S)-3-(4-(5-((((1-cyclobutylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (isomer 1) 49

LCMS, [M + H]⁺ = 471.3 ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.62 (m, 2H), 7.03(br d, J = 3.3 Hz, 2H), 5.32 (br d, J = 2.9 Hz, 2H), 4.87- 4.56 (m, 1H),4.19 (br s, 3H), 3.07-2.86 (m, 1H), 2.67 (br s, 3H), 2.49- 1.49 (m,16H), 1.05- 0.93 (m, 3H) hLPA1 IC₅₀ = 14 nM. Example 1(1S,3S)-3-(4-(5-((((1- cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid (isomer 2) 50

LCMS, [M + H]⁺ = 460.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (br. s., 1H),8.09-7.93 (m, 1H), 7.55 (d, J = 7.9 Hz, 1H), 5.62 (d, J = 16.8 Hz, 2H),4.78 (br. s., 1H), 4.11 (br. s., 3H), 3.29-3.00 (m, 2H), 2.76 (d, J =17.7 Hz, 3H), 2.64 (br. s., 1H), 1.97-1.45 (m, 8H), 1.40- 1.14 (m, 2H),0.88 (d, J = 4.9 Hz, 3H), 0.67 (d, J = 5.2 Hz, 3H) hLPA1 IC₅₀ = 12 nM.Example 1 (1S,3S)-3-((6-(5- (((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 51

LCMS, [M + H]⁺ = 457.3 ¹H NMR (400 MHz, CD₃CN) δ 7.64-7.44 (m, 2H), 6.89(d, J = 8.8 Hz, 2H), 5.10 (s, 2H), 4.61-4.49 (m, 1H), 3.94 (s, 3H),2.70-2.52 (m, 4H), 1.96-1.85 (m, 1H), 1.75-1.35 (m, 8H), 0.97 (br. s.,3H), 0.75 (br. s., 1H), 0.44-0.25 (m, 4H) hLPA1 IC₅₀ = 24 nM. In vivoacute histamine assay: −73% histamine at a 3 mg/kg dose of Example 51Example 1 (1S,3S)-3-(4-(5-(((((R)-1- cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid 52

LCMS, [M + H]⁺ = 457.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.54 (d, J = 8.2 Hz,2H), 6.96 (d, J = 8.2 Hz, 2H), 5.18 (br. s., 2H), 4.59 (br. s., 1H),3.99 (s, 3H), 2.62 (br. s., 3H), 2.51 (br. s., 1H), 1.74-1.31 (m, 8H),1.06- 0.90 (m, 3H), 0.87- 0.71 (m (m, 4H), 1H), 0.43-−0.30 (m, 4H) hLPA1IC₅₀ = 197 nM. Example 3 (1S,3S)-3-(4-(5-(((((S)-1-cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid 53

LCMS, [M + H]⁺ = 445.2 ¹HNMR (500 MHz, DMSO-d₆) δ 7.68 (br. s., 2H),7.08 (d, J = 8.2 Hz, 2H), 5.31 (s, 2H), 4.72 (br. s., 1H), 4.12 (s, 3H),3.08-2.93 (m, 2H), 2.80 (d, J = 15.3 Hz, 3H), 2.67 (br. s., 1H),2.03-1.48 (m, 9H), 0.88-0.64 (m, 6H) hLPA1 IC₅₀ = 440 nM. Example 1(1S,3S)-3-(4-(5- (((isobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) 54

LCMS, [M + H]⁺ = 471.2 ¹H NMR (400 MHz, CDCl₃) δ 7.60 (t, J = 9.4 Hz,2H), 6.93 (d, J = 7.5 Hz, 2H), 5.21 (s, 2H), 4.61 (br. s., 1H), 4.10 (d,J = 2.2 Hz, 4H), 3.84 (dd, J = 10.3, 6.6 Hz, 1H), 2.98- 2.76 (m, 1H),2.69- 2.53 (m, 3H), 2.34-2.19 (m, 1H), 2.08 (d, J = 13.9 Hz, 1H),2.00-1.40 (m, 12H), 0.90 (dd, J = 17.7, 6.7 Hz, 3H) hLPA1 IC₅₀ = 19 nM.Example 2 (1S,3S)-3-(4-(5-((((1- cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) 55

LCMS, [M + H]⁺ = 457.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (br. s., 2H),7.20 (d, J = 7.6 Hz, 2H), 5.43 (br. s., 2H), (br. s., 1H), 4.24 (s, 3H),3.54-3.30 (m, 3H), 2.93 (d, J = 9.2 Hz, 3H), 2.79 (br. s., 1H), 2.17-1.30 (m, 10H), 0.76-−0.06 (m, 4H) hLPA1 IC₅₀ = 41 nM. Example 3(rac)-trans-3-(4-(5-((((2- cyclopropylethyl)(methypcarbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid 56

LCMS, [M + H]⁺ = 473.2 ¹H NMR (400 MHz, CD₃CN) δ 7.61 (d, J = 15.2 Hz,2H), 7.05 (br. s., 1H), 5.33 (br. s., 2H), 4.79 (br. s., 1H), 4.14 (s,3H), 3.35-3.13 (m, 2H), 2.91-2.72 (m, 4H), 2.36- 2.26 (m, 3H), 2.14 (d,J = 13.4 Hz, 1H), 1.89- 1.26 (m, 10H), 1.02- 0.68 (m, 6H) hLPA1 IC₅₀ = 3nM. Example 2 (1S,3S)-3-(4-(5- (((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylphenoxy)cyclohexane-1-carboxylic acid 57

LCMS, [M + H]⁺ = 459.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.67 (t, J = 9.6 Hz,2H), 7.16- 6.98 (m, 2H), 5.31 (s, 2H), 4.72 (br. s., 1H), 4.12 (s, 3H),2.66 (d, J = 10.1 Hz, 1H), 2.04- 1.47 (m, 10H), 1.46- 1.28 (m, 3H),1.19-0.65 (m, 9H) hLPA1 IC₅₀ = 142 nM. Example 2 trans-3-(4-(1-methyl-5-(((methyl(pentan-2- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid (diastereomericmixture) 58

LCMS, [M + H]+ = 459.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.70 (d, J = 8.2 Hz,2H), 7.08 (d, J = 7.6 Hz, 2H), 5.31 (br. s., 2H), 4.72 (br. s., 1H),4.12 (s, 3H), 3.23-3.08 (m, 2H), 2.79 (d, J = 13.7 Hz, 3H), 2.67 (br.s., 1H), 2.03-1.01 (m, 14H), 0.93-0.69 (m, 3H) hLPA1 IC₅₀ = 250 nM.Example 2 (rac)-trans-3-(4-(1-methyl-5-(((methyl(pentyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid 59

LCMS, [M + H]⁺ = 431.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.68 (br. s., 2H),7.09 (d, J = 8.5 Hz, 2H), 5.31 (s, 2H), 4.72 (br. s., 1H), 4.12 (s, 3H),3.20-3.07 (m, 2H), 2.80 (d, J = 9.8 Hz, 3H), 2.67 (br. s., 1H),2.05-1.31 (m, 10H), 0.84-0.65 (m, 3H) hLPA1 IC₅₀ = 1880 nM. Example 2(rac)-trans-3-(4-(1-methyl-5- (((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1- carboxylic acid 60

LCMS, [M + H]⁺ = 479.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.80-7.55 (m, 2H),7.44-6.96 (m, 7H), 5.48-5.16 (m, 2H), 4.70 (br. s., 1H), 4.41 (d, J =12.8 Hz, 2H), 4.21- 3.94 (m, 3H), 2.90-2.73 (m, 3H), 2.70-2.61 (m, 1H),2.04-1.48 (m, 8H) hLPA1 IC₅₀ = 130 nM. Example 2 (rac)-trans-3-(4-(5-(((benzyl(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid 61

LCMS, [M + H]⁺ = 443.2 ¹H NMR (500 MHz, ¹H NMR (500 MHz, DMSO-d6) δ7.66-7.46 (m, 2H), 7.08-6.86 (m, 2H), 5.28-5.11 (m, 2H), 4.68-4.59 (m,1H), 4.10- 3.94 (m, 3H), 3.08- 2.91 (m, 3H), 2.85-2.71 (m, 3H),2.65-2.54 (m, 1H), 1.97-1.39 (m, 8H), 0.96-0.67 (m, 1H), 0.46- 0.22 (m,2H), 0.16 to −0.08 (m, 2H) hLPA1 IC₅₀ = 273 nM. Example 2(rac)-trans-3-(4-(5- ((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-carboxylic acid 62

LCMS, [M + H]⁺ = 459.2 ¹H NMR (400 MHz, CD₃CN) δ 7.80-7.65 (m, 2H),7.12-6.96 (m, 2H), 5.35-5.24 (m, 2H), 4.78-4.70 (m, 1H), 5.07- 4.33 (m,1H), 4.20- 4.06 (m, 3H), 3.37-3.14 (m, 2H), 2.93-2.72 (m, 4H), 2.13-2.02(m, 1H), 1.92-1.22 (m, 10H), 0.99-0.74 (m, 6H) hLPA1 IC₅₀ = 1290 nM.Example 2 (1R,3R)-3-(4-(5- (((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-carboxylic acid 63

LCMS, [M + H]⁺ = 473.2 ¹H NMR (400 MHz, CD₃CN) δ 7.65-7.46 (m, 2H), 7.04(d, J = 8.4 Hz, 1H), 5.29 (br. s., 2H), 4.78 (br. s., 1H), 4.13 (s, 3H),3.30-3.19 (m, 2H), 2.88-2.74 (m, 4H), 2.30 (s, 3H), 2.18-2.09 (m, 1H),1.80-1.25 (m, 11H), 0.96-0.70 (m, 6H) hLPA1 IC₅₀ = 701 nM. Example 2(1R,3R)-3-(4-(5- (((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylphenoxy)cyclohexane-1-carboxylic acid 64

LCMS, [M + H]⁺ = 445.2 (500 MHz, DMSO-d₆) δ 7.76-7.57 (m, 2H), 7.17-6.94 (m, 2H), 5.42- 5.23 (m, 2H), 4.77-4.62 (m, 1H), 4.19-4.04 (m, 3H),3.28-3.06 (m, 2H), 2.88-2.75 (m, 3H), 2.71- 2.59 (m, 1H), 2.01- 1.03 (m,13H), 0.92- 0.68 (m, 3H) hLPA1 IC₅₀ = 32 nM. Example 1(rac)-trans-3-(4-(5- (((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1- carboxylic acid65

LCMS, [M + H]⁺ = 457.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.54 (d, J = 8.5 Hz,2H), 6.96 (d, J = 8.2 Hz, 2H), 5.19 (br. s., 2H), 4.60 (br. s., 1H),3.99 (s, 3H), 2.63 (br. s., 4H), 2.60-2.51 (m, 1H), 1.95-1.34 (m, 8H),1.06- 0.71 (m, 4H), 0.47- 0.29 (m, 4H) hLPA1 IC₅₀ = 80 nM. Example 1trans-3-(4-(5-((((1- cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) 66

LCMS, [M + H]⁺ = 457.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.70 (d, J = 7.9 Hz,2H), 7.09 (d, J = 8.5 Hz, 2H), 5.31 (br. s., 2H), 4.72 (br. s., 1H),4.12 (br. s., 3H), 3.31- 3.13 (m, 2H), 2.78 (d, J = 11.0 Hz, 3H), 2.67(br. s., 1H), 2.03-1.45 (m, 15H) hLPA1 IC₅₀ = 68 nM. Example 1(rac)-trans-3-(4-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid 67

LCMS, [M + H]⁺ = 471.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.81-7.58 (m, 2H),7.12-7.03 (m, 2H), 5.43-5.17 (m, 2H), 4.71 (br. s., 1H), 4.12 (d, J =12.2 Hz, 3H), 4.06- 3.74 (m, 1H), 3.00 (s, 3H), 2.66 (br. s., 1H),2.03-1.44 (m, 15H), 0.94-0.81 (m, 3H) hLPA1 IC₅₀ = 109 nM. Example 1trans-3-(4-(5-((((1- cyclobutylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) 68

LCMS, [M + H]⁺ = 445.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.75-7.60 (m, 2H),7.08 (d, J = 8.9 Hz, 2H), 5.31 (s, 2H), 4.71 (br. s., 1H), 4.11 (s, 3H),4.05-3.73 (m, 1H), 2.73-2.57 (m, 4H), 2.02- 1.27 (m, 10H), 1.08- 0.92(m, 3H), 0.76-0.57 (m, 3H) hLPA1 IC₅₀ = 320 nM. Example 1(trans)-3-(4-(5-(((sec- butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)eyelohexane-1- carboxylic acid(diastereomeric mixture) 69

LCMS, [M + H]⁺ = 473.0 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.52 (d, J = 8.6 Hz, 1H), 5.62 (d, J = 19.4 Hz, 2H), 4.09 (d, J =7.2 Hz, 3H), 3.33- 3.04 (m, 2H), 2.82-2.67 (m, 3H), 2.36 (br. s., 3H),2.45-2.16 (m, 1H), 2.08- 1.15 (m, 14H) hLPA1 IC₅₀ = 57 nM. Example 2(using intermediate 2) (3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic-1-dacid (homochiral) 70

LCMS, [M + H]⁺ = 475.3 ¹H NMR (400 MHz, CDCl₃ δ 7.51-7.32 (m, 2H), 7.03(t, J = 8.5 Hz, 1H), 5.28-5.12 (m, 2H), 4.62 (br. s., 1H), 4.11 (s, 3H),3.41 (d, J = 9.0 Hz, 1H), 3.19 (br. s., 1H), 2.98-2.69 (m, 4H), 2.11 (d,J = 13.6 Hz, 1H), 2.01- 1.67 (m, 4H), 1.65- 1.49 (m, 3H), 1.11 (d, J =6.6 Hz, 3H), 0.78 (br. s., 1H), 0.57-−0.15 (m, 3H) hLPA1 IC₅₀ = 10 nM.Example 1 (1S,3S)-3-(4-(5-(((((R)-1- cyclopropylethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-fluorophenoxy)cyclohexane-1- carboxylic acid 71

LCMS, [M + H]⁺ = 459.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.88-7.56 (m, 2H),7.08 (br. s., 2H), 5.31 (br. s., 2H), 4.71 (br. s., 1H), 4.12 (s, 3H),3.29- 3.05 (m, 2H), 2.79 (d, J = 17.1 Hz, 3H), 2.70- 2.60 (m, 1H),2.05-1.19 (m, 11H), 0.93-0.69 (m, 6H) hLPA1 IC₅₀ = 13 nM. Example 2(rac)-trans-3-(4-(5- (((isopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexane-1-carboxylic acid 72

LCMS, [M + H]⁺ = 534.4 ¹H NMR (400 MHz, CD₃OD) δ 7.67 (d, J = 8.8 Hz,2H), 7.09 (d, J = 8.8 Hz, 2H), 5.37 (s, 2H), 4.20 (s, 3H), 3.20 (s, 3H),2.78-2.89 (m, 5H), 1.59- 2.10 (m, 17H). hLPA1 IC₅₀ = 2780 nM. Example 7(1-Methyl-4-(4-(((1R,3R)-3- ((methylsulfonyl)carbamoyl)cyclohexyl)oxy)phenyl)-1H-1,2,3-triazol-5- yl)methyl cyclopentyl (methyl)carbamate73

LCMS, [M + H]⁺ = 443.5 ¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J = 8.00 Hz,2H), 7.08 (d, J = 8.00 Hz, 2H), 5.33 (s, 2H), 4.72-4.74 (m, 1H), 4.18(s, 3H), 2.78-2.84 (m, 4H), 2.08-2.14 (m, 5H), 1.82-1.93 (m, 3H),1.41-1.79 (m, 7H). hLPA1 IC₅₀ = 62 nM. Example 10 (1S,3S)-3-(4-(5-(((cyclobutyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid 74

LCMS, [M + H]⁺ = 483.2 ¹H NMR (400 MHz, CD₃OD) δ 7.66 (d, J = 8.80 Hz,2H), 7.09 (d, J = 8.80 Hz, 2H), 5.36 (s, 2H), 4.83-4.89 (m, 1H), 4.19(s, 3H), 2.90-2.97 (m, 3H), 2.70-2.87 (m, 2H), 2.08-2.15 (m, 1H),1.90-1.99 (m, 3H), 1.62- 1.74 (m, 4H), 1.05- 1.09 (m, 2H), 0.50-0.70 (m,2H), 0.12-0.43 (m, 6H). hLPA1 IC₅₀ = 100 nM. Example 3 (1S,3S)-3-(4-(5-((((Dicyclopropylmethyl)(methyl) carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)phenoxy)cyclohexanecarboxylic acid 75

LCMS, [M + H]⁺ = 471.2 ¹H NMR (400 MHz, CD₃OD) δ 7.70-7.80 (m, 1H),7.60-7.70 (m, 1H), 7.08 (m, 2H), 5.30- 5.39 (m, 2H), 4.81-4.83 (m, 1H),4.18-4.21 (m, 3H), 2.89 (s, 3H), 2.79- 2.82 (m, 1H), 2.06-2.12 (m, 1H),1.80-2.00 (m, 3H), 1.60-1.80 (m, 4H), 1.20-1.50 (m, 4H), 0.80- 0.90 (m,2H), 0.70- 0.80 (m, 3H), 0.60-0.70 (m, 2H). hLPA1 IC₅₀ = 20 nM. Example3 (1S,3S)-3-(4-(1-methyl-5- (((methyl(1-propylcyclopropyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid 76

LCMS, [M + H]⁺ = 459.2 ¹H NMR (400 MHz, CD₃OD) δ 7.60-7.70 (m, 2H),7.10- 7.00 (m, 2H), 5.37 (s, 2H), 4.70- 4.80 (m, 1H), 4.18 (s, 3H),2.75-2.85 (m, 1H), 2.60-2.70 (m, 3H), 2.08- 2.15 (m, 1H), 1.90- 2.00 (m,3H), 1.60-1.75 (m, 5H), 1.40-1.50 (m, 4H), 0.71-0.81 (m, 6H). hLPA1 IC₅₀= 47 nM. Example 3 (1S,3S)-3-(4-(1-methyl-5- (((methyl(pentan-3-yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)phenoxy)cyclohexane-1-carboxylic acid 77

LCMS, [M + H]⁺ = 460.4 ¹H NMR (400 MHz, CD₃OD) δ 8.30-8.46 (m, 1H),7.90-7.97 (m, 1H), 7.51-7.65 (m, 1H), 5.70 (d, J = 10.8 Hz, 1H),4.50-4.60 (m, 1H), 4.20 (s, 3H), 3.62-3.93 (m, 1H), 2.71-2.82 (m, 1H),2.60-2.70 (m, 3H), 1.82- 2.10 (m, 4H), 1.57- 1.79 (m, 4H), 1.36-1.49 (m,5H), 0.82 (t, J = 7.2 Hz, 3H), 0.67 (t, J = 7.6 Hz, 3H). hLPA1 IC₅₀ =242 nM. Example 1 (1S,3S)-346-(1-methyl-5- (((methyl(pentan-3-yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 78

LCMS, [M + H]⁺ = 474.4 ¹H NMR (400 MHz, CD₃OD) δ 8.30-8.50 (m, 1H),7.94-8.05 (m, 1H), 7.53 (d, J = 8.40 Hz, 1H), 5.66 (s, 2H), 4.82- 4.86(m, 1H), 4.20 (s, 3H), 2.75-2.90 (m, 4H), 1.90-2.20 (m, 4H), 1.60- 1.90(m, 6H), 1.31 (s, 6H), 1.15-1.21 (m, 2H), 0.80 (t, J = 6.40 Hz, 3H).hLPA1 IC₅₀ = 27 nM. Example 1 (1S,3S)-3-((6-(1-methyl-5-(((methyl(2-methylpentan-2- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 79

LCMS, [M + H]⁺ = 444.2 ¹H NMR (400 MHz, CD₃OD) δ 8.35-8.40 (m, 1H), 7.97(d, J = 9.20 Hz, 1H), 7.53 (dd, J = 8.8 & 2.8 Hz, 1H), 5.70 (s, 2H),4.80-4.85 (m, 1H), 4.21 (d, J = 16.00 Hz, 3H), 2.81-2.87 (m, 4H),1.91-2.11 (m, 4H), 1.63- 1.87 (m, 4H), 1.12 (s, 3H), 0.56-0.87 (m, 4H).hLPA1 IC₅₀ = 45 nM. Example 1 (1S,3S)-3-((6-(1-methyl-5- (((methyl(1-methylcyclopropyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 80

LCMS, [M + H]⁺ = 484.4 ¹H NMR (400 MHz, CD₃OD) δ 8.32-8.40 (m, 1H),7.97-8.04 (m, 1H), 7.53 (d, J = 8.00 Hz, 1H), 5.60-5.80 (m, 2H), 4.82-4.87 (m, 1H), 4.19 (s, 3H), 2.91 (d, J = 14.80 Hz, 3H), 2.79-2.81 (m,2H), 2.40-2.50 (m, 1H), 1.91-2.10 (m, 4H), 1.63- 1.79 (m, 4H), 0.99-1.07(m, 2H), 0.51-0.68 (m, 2H), 0.13-0.41 (m, 5H). hLPA1 IC₅₀ = 60 nM.Example 3 (1S,3S)-3-((6-(5- ((((Dicyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid 81

LCMS, [M + H]⁺ = 472.2 ¹H NMR (400 MHz, CD₃OD) δ 8.31-8.39 (m, 1H),7.94-8.02 (m, 1H), 7.52 (d, J = 8.40 Hz, 1H), 5.67-5.70 (m, 2H), 4.81-4.89 (m, 1H), 4.40- 4.50, m, 1H), 4.20 (d, J = 16.40 Hz, 3H), 2.72- 2.87(m, 3H), 1.85-2.10 (m, 4H), 1.60-1.73 (m, 4H), 1.10-1.40 (m, 4H),0.84-0.90 (m, 2H), 0.65- 0.76 (m, 4H), 0.56- 0.59 (m, 1H). hLPA1 IC₅₀ =61 nM. Example 3 (1S,3S)-346-(1-methyl-5- (((methyl(1-propylcyclopropyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 82

LCMS, [M + H]⁺ = 460.9 ¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (br. s., 1H),7.99 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 6.6 Hz, 1H), 5.85-5.40 (m, 2H),4.78 (br. s., 1H), 3.59- 2.83 (m, 2H), 2.79-2.60 (m, 4H), 2.03-1.36 (m,14H), 1.16 (t, J = 7.2 Hz, 1H) hLPA1 IC₅₀ = 28 nM. Example 4(1S,3S)-3-((6-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-(methyl-d3)-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 83

LCMS, [M + H]⁺ = 474.4 ¹H NMR (400 MHz, CD₃OD) δ 7.68 (d, J = 8.0 Hz,1H), 7.35-7.40 (m, 1H), 5.55-5.65 (m, 2H), 4.20-4.30 (m, 1H), 4.07 (s,3H), 3.75-3.90 (m, 1H), 3.55-3.70 (m, 1H), 2.50-2.70 (m, 3H), 2.20-2.40(m, 3H), 1.80- 2.10 (m, 3H), 1.94 (s, 3H), 1.55-1.84 (m, 3H), 1.10-1.40(m, 3H), 0.70 (t, J = 7.6 Hz, 3H), 0.55 (t, J = 7.2 Hz, 3H). hLPA1 IC₅₀= 92 nM. Example 2 (1S,3S)-3-((2-Methyl-6-(1-methyl-5-(((methyl(pentan-3- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexanecarboxylic acid 84

LCMS, [M + H]⁺ = 488.2 ¹H NMR (400 MHz, CD₃OD) δ 7.70 (d, J = 8.4, 1H),7.32 (d, J = 8.4 Hz, 1H), 5.56 (s, 2H), 4.07 (s, 3H), 2.74 (s, 3H),2.62-2.69 (m, 1H), 2.40 (s, 3H), 1.98-2.05 (m, 1H), 1.80-1.90 (m, 3H),1.45-1.70 (m, 5H), 1.20 (s, 6H), 1.01-1.10 (m, 3H), 0.71-0.79 (m, 1H),0.60-0.70 (m, 3H). hLPA1 IC₅₀ = 69 nM. Example 1(1S,3S)-3((2-methyl-6-(1-methyl-5- (((methyl(2-methylpentan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid 85

LCMS, [M + H]⁺ = 458.2 ¹H NMR (400 MHz, CD₃OD) δ 7.81 (d, J = 8, 1H)7.44 (d, J = 8 Hz, 1 H) 5.71 (s, 2 H) 4.79- 4.81 (m, 1 H) 4.13-4.26 (m,3H) 2.74-2.88 (m, 4 H) 2.51 (s, 3 H) 2.06- 2.18 (m, 1 H) 1.86-1.96 (m, 3H) 1.62-1.83 (m, 4 H) 1.11 (br. s. 3 H) 0.43-0.85 (m, 4 H) hLPA1 IC₅₀ =58 nM. Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(1-methylcyclopropyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 86

LCMS, [M + H]⁺ = 498.3 ¹H NMR (400 MHz, CD₃OD) δ 7.79 (d, J = 8.0 Hz,1H), 7.42 (d, J = (8.0 Hz, 1H), 5.60-5.70 (m, 2H), 4.17 (s, 3H), 2.90(d, J = 13.2 Hz, 3H), 2.60-2.80 (m, 3H), 2.49 (s, 3H), 2.40-2.55 (m,3H), 2.05-2.15 (m, 1H), 1.60-1.80 (m, 4H), 1.20- 1.40 (m, 2H), 0.90-1.10 (m, 2H), 0.45-0.65 (m, 2H), 0.30-0.40 (m, 2H), 0.10-0.30 (m, 2H).hLPA1 IC₅₀ = 54 nM. Example 1 (1S,3S)-3-((6-(5-((((Dicyclopropylmethyl)(methyl) carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexanecarboxylic acid87

LCMS, [M + H]⁺ = 486.0 ¹H NMR (400 MHz, CD₃OD) δ 7.77-7.86 (m, 1 H) 7.44(d, J = 8.4 Hz, 1 H) 5.71 (d, J = 11.6 Hz, 2H) 4.81-4.84 (m, 1 H), 4.2(d, J = 8.4 Hz, 1 H), 2.74-2.90 (m, 4H), 2.51 (s, 3H), 2.10-2.15 (m,1H), 1.91-1.97 (m, 3H), 1.66-1.74 (m, 4H), 1.28- 1.37 (m, 2H), 1.12-1.20(m, 2H), 0.84-0.93 (m, 2H), 0.68-0.71(m, 5H), 0.51-0.53 (m, 2H). hLPA1IC₅₀ = 36 nM. Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(1-propylcyclopropyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 88

LCMS, [M + H]⁺ = 490.3 ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 8.6 Hz,1H), 7.24-7.17 (m, 1H), 5.71-5.62 (m, 2H), 4.71 (tt, J = 6.8, 3.7 Hz,1H), 4.58-4.13 (m, 1H), 4.07 (s, 3H), 2.65 (br. s., 3H), 2.52-2.38 (m,4H), 2.24-1.32 (m, 15H); hLPA1 IC₅₀ = 32 nM. Example 11(rac)-trans-3-((6-(5- (((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-l-carboxylic acid 89

LCMS, [M + H]⁺ = 476.3 ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J = 2.5 Hz,1H), 8.05 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.9, 2.6 Hz, 1H), 5.50 (s,2H), 4.89-4.75 (m, 1H), 4.55- 4.44 (m, 1H), 4.10 (s, 3H), 2.64 (br. s.,3H), 2.56-2.37 (m, 4H), 2.19- 1.37 (m, 15H) hLPA1 IC₅₀ = 32 nM. Example11 (rac)-trans-3-((6-(5- (((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)pyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylic acid 90

LCMS, [M + H]⁺ = 476.3 ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J = 2.5 Hz,1H), 8.18 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 5.56 (s, 2H),4.92 (br. s., 1H), 4.65- 4.50 (m, 1H), 4.21 (d, J = 3.0 Hz, 3H), 2.85(d, J = 17.1 Hz, 3H), 2.66- 2.41 (m, 4H), 2.29-1.48 (m, 15H) hLPA1 IC₅₀= 14 nM. Example 11 (rac)-trans-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)-1- fluorocyclohexane-1-carboxylic acid 91

LCMS, [M + H]⁺ = 473.4 ¹H NMR (500 MHz, CDCl₃) δ 8.11 (d, J = 8.8 Hz,1H), 7.80 (t, J = 8.9 Hz, 1H), 5.70-5.42 (m, 2H), 4.86 (br. s., 1H),4.20 (d, J = 1.7 Hz, 3H), 3.39-3.26 (m, 3H), 2.90 (d, J = 7.7 Hz, 3H),2.77- 2.69 (m, 3H), 2.19-1.63 (m, 15H) hLPA1 IC₅₀ = 18 nM. Example 2(rac)-trans-3-((6-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 92

LCMS, [M + H]⁺ = 472.3 ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J = 8.6 Hz,1H), 7.66 (t, J = 8.6 Hz, 1H), 5.72 (d, J = 14.5 Hz, 1H), 5.47 (d, J =14.3 Hz, 1H), 4.58 (br. s., 1H), 4.21 (s, 3H), 3.40-3.19 (m, 2H), 2.90(s, 3H), 2.70 (d, J = 2.6 Hz, 3H), 2.64-2.46 (m, 2H), 2.31- 1.48 (m,14H) hLPA1 IC₅₀ = 76 nM. Example 2 (rac)-cis-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 93

LCMS, [M + H]⁺ = 475.1 ¹H NMR (500 MHz, CDCl₃) δ 8.10 (br. s., 1H), 7.87(br. s., 1H), 5.90-5.21 (m, 2H), 4.21 (br. s., 3H), 3.30 (t, J = 8.0 Hz,2H), 2.85 (br. s., 1H), 2.73 (br. s., 3H), 2.63- 2.47 (m, 1H), 2.24-1.52(m, 16H) hLPA1 IC₅₀ = 20 nM. Example 4 (1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl- d3)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 94

LCMS, [M + H]⁺ = 471.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.58 (br. S., 2H),7.05 (d, J = 8.0 Hz, 2H), 6.00 (d, J = 6.9 Hz, 1H), 4.69 (br. S., 1H),4.40-4.22 (m, 1H), 4.13 (s, 3H), 2.65 (br. S., 4H), 1.98-1.35 (m, 19H)hLPA1 IC₅₀ = 241 nM. Example 14 (1S,3S)-3-(4-(5-(1-((cyclopentyl(methyl)carbamoyl)oxy) ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexane-1- carboxylic acid 95

LCMS, [M + H]⁺ = 472.3 ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 8.1 Hz,1H), 7.16 (dd, J = 8.3, 3.6 Hz, 1H), 5.74 (br. S., 2H), 4.32-4.18 (m,1H), 4.13 (br. S., 3H), 3.35- 3.11 (m, 2H), 2.92-2.75 (m, 3H), 2.56-2.24(m, 5H), 2.17-1.35 (m, 15H) hLPA1 IC₅₀ = 1152 nM. Example 1(Cis)-3-((6-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid; Enantiomer A 96

LCMS, [M + H]⁺ = 472.3 ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J = 8.6 Hz,1H), 7.11 (d, J = 8.6 Hz, 1H), 5.67 (br. s., 2H), 4.23-4.12 (m, 1H),4.06 (br. s., 3H), 3.31-3.01 (m, 2H), 2.86-2.65 (m, 3H), 2.42-2.30 (m,4H), 2.16-1.31 (m, 15H) hLPA1 IC₅₀ = 20 nM. Example 1 (Cis)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acidEnantiomer B 97

LCMS, [M + H]⁺ = 472.3 ¹H NMR (400 MHz, CDCl₃) δ 8.03-7.90 (m, 1H), 7.23(d, J = 8.6 Hz, 1H), 5.77 (br d, J = 5.3 Hz, 2H), 4.72 (br s, 1H), 4.16(br s, 3H), 3.38- 3.15 (m, 2H), 2.90 (br s, 3H), 2.80 (br s, 2H), 2.59(br s, 1H), 2.45-2.36 (m, 1H), 2.23-2.10 (m, 1H), 2.08-1.52 (m, 14H)hLPA1 IC₅₀ = 10 nM. Example 1 (1R,3R)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 98

LCMS, [M + H]⁺ = 512.3 ¹H NMR (600 MHz, DMSO-d₆) δ 7.84 (d, J = 5.2 Hz,1H), 7.46 (br. s., 1H), 7.41-6.79 (m, 4H), 5.87-5.59 (m, 2H), 4.78 (br.s., 1H), 4.51- 4.26 (m, 2H), 4.15-3.91 (m, 3H), 3.53-3.37 (m, 1H),2.87-2.69 (m, 3H), 2.67-2.58 (m, 1H), 2.46- 2.30 (m, 3H), 2.07- 1.44 (m,8H) hLPA1 IC₅₀ = 19 nM. Example 1 (1S,3S)-3-((6-(5-((((2-fluorobenzyl)(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 99

LCMS, [M + H]⁺ = 486.3 ¹H NMR (600 MHz, DMSO-d₆) δ 7.47 (d, J = 8.5 Hz,1H), 6.98 (d, J = 9.1 Hz, 1H), 5.65 (br. s., 2H), 4.77 (br. s., 1H),4.07 (s, 3H), 3.51 (br. s., 4H), 2.66-2.57 (m, 1H), 2.40 (br. s., 3H),2.29- 2.19 (m, 1H), 2.05-1.97 (m, 1H), 1.89-1.43 (m, 14H), 1.25 (d, J =7.3 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H) hLPA1 IC₅₀ = 144 nM. Example 1(1S,3S)-3-((6-(5-((((1- cyclobutylpropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (diastereomeric mixture) 100

LCMS, [M + H]⁺ = 520.0 ¹H NMR (400 MHz, CD₃OD) δ 7.60-7.69 (m, 1 H)7.01-7.34 (m, 5 H) 6.78-6.88 (m, 1 H) 5.60-5.68 (m, 2 H) 4.08- 4.14 (m,1 H) 3.76- 3.86 (m, 3 H) 2.88-2.94 (m, 3 H) 2.80-2.83 (m, 1 H) 2.32-2.44(m, 3H) 1.86-1.92 (m, 4 H) 1.54- 1.67 (m, 4 H) 1.18- 1.27 (m, 4 H) hLPA1IC₅₀ = 70 nM. Example 5 (1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(1-phenylcyclopropyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 101

LCMS, [M + H]⁺ = 500.0 ¹H NMR (400 MHz, CD₃OD) δ 7.60-7.69 (m, 1 H)7.01-7.34 (m, 5 H) 6.78-6.88 (m, 1 H) 5.60-5.68 (m, 2 H) 4.08- 4.14 (m,1 H) 3.76- 3.86 (m, 3 H) 2.88-2.94 (m, 3 H) 2.80-2.83 (m, 1 H) 2.32-2.44(m, 3H) 1.86-1.92 (m, 4 H) 1.54- 1.67 (m, 4H) 1.18- 1.27 (m, 4 H) hLPA1IC₅₀ = 49 nM. Example 5 (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(3,3,3- trifluoropropyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid102

LCMS, [M + H]⁺ = 469.9 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.4 Hz,1H), 7.48 (d, J = 8.6 Hz, 1H), 5.61 (s, 2H), 4.87-4.69 (m, 1H), 4.10 (s,3H), 2.71 (br. S., 3H), 2.55 (s, 3H), 2.40 (s, 3H), 2.07-1.47 (m, 15H)hLPA1 IC₅₀ = 53 nM. Example 1 (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1- yl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 103

LCMS, [M + H]⁺ = 508.2 ¹H NMR (400 MHz, CD₃OD) δ 7.84-7.88 (m, 1 H) 7.46(br. s., 1 H) 7.12-7.31 (m, 4 H) 6.97- 7.01 (m, 1 H) 5.60- 5.73 (m, 2H)4.80 (br. s., 1 H) 4.12 (br. s., 3 H) 3.46-3.53 (m, 3 H) 2.74- 2.85 (m,4 H) 2.63 (d, J = 7.03 Hz, 1 H) 2.46 (br. s., 3 H) 2.09 (br. s., 1 H)1.94 (br. s., 3 H) 1.61- 1.73 (m, 4 H) hLPA1 IC₅₀ = 119 nM. Example 5(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(phenethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4- yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 104

LCMS, [M + H]⁺ = 446.1 ¹H NMR (400 MHz, CD₃OD) δ 7.81 (d, J = 8.53 Hz, 1H) 7.44 (d, J = 8.53 Hz, 1 H) 5.71 (br. s., 2 H) 4.81 (br. s., 1 H) 4.19(s, 3 H) 3.09-3.17 (m, 2 H) 2.81-2.90 (m, 4 H) 2.51 (s, 3 H) 2.14 (br.s., 1 H) 1.88-1.92 (m, 3 H) 1.68-1.71 (m, 4 H) 1.56 (br. s., 2 H) 0.88(d, J = 7.03 Hz, 3 H) hLPA1 IC₅₀ = 19 nM Example 5(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylicacid 105

LCMS, [M + H]+ = 456.3 hLPA1 IC₅₀ = 576 nM. Example 3 (1S,3S)-3-((6-(5-(((bicyclo[1.1.1]pentan-1- ylcarbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 106

LCMS, [M + H]⁺ = 486.1 ¹H NMR (400 MHz, CD₃OD) δ 7.79 (d, J = 8.53 Hz, 1H) 7.44 (d, J = 8.53 Hz, 1 H) 5.66 (s, 2 H) 4.19 (s, 3H) 2.68 (d, J =6.02 Hz, 1 H) 2.52 (s, 3 H) 2.12 (d, J = 13.05 Hz, 3 H) 1.94 (br. s.,3H) 1.58-1.79 (m, 5H) 1.31 (br. s., 6 H) 1.13 (br. s., 3 H) 0.93-0.96(m, 3 H) hLPA1 IC₅₀ = 67 nM. Example 5 (1S,3S)-3-((6-(5-((((1,3-dimethylcyclobutyl)(methyl)carbamoyl) yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acidEnantiomer A 107

LCMS, [M + H]⁺ = 486.1 ¹H NMR (400 MHz, CD₃OD) δ ppm 7.79 (d, J = 8.53Hz, 1 H) 7.44 (d, J = 8.53 Hz, 1 H) 5.66 (s, 2 H) 4.19 (s, 3H) 2.68 (d,J = 6.02 Hz, 1 H) 2.52 (s, 3 H) 2.12 (d, J = 13.05 Hz, 3 H) 1.94 (br. s.3H) 1.58-1.79 (m, 5H) 1.31 (br. s. 6 H) 1.13 (br. s., 3 H) 0.93-0.96 (m,3 H) hLPA1 IC₅₀ = 70 nM. Example 5 (1S,3S)-3-((6-(5-((((1,3-dimethylcyclobutyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acidEnantiomer B 108

LCMS, [M + H]⁺ = 458.0 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.2 Hz,1H), 7.58- 7.37 (m, 1H), 7.29 (br. s., 1H), 5.64 (s, 2H), 4.77 (br. s.,1H), 4.07 (s, 3H), 3.01 (t, J = 6.0 Hz, 2H), 2 44-2.31 (m, 4H), 2.05-1.40 (m, 15H) hLPA1 IC₅₀ = 108 nM. Example 1 (1S,3S)-3-((6-(5-((((cyclobutylmethyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 109

LCMS, [M + H]⁺ = 486.2 ¹H NMR (400 MHz, DMSO-d₆) δ 6.97-7.04 (m, 1 H)6.60-6.67 (m, 1 H) 4.89 (s, 2 H) 3.99- 4.01 (m, 1 H) 3.38 (s, 3 H)2.39-2.43 (m, 1 H) 2.26-2.30 (m, 1 H) 2.08 (s, 3 H) 1.70 (s, 3 H) 1.28-1.33 (m, 1 H) 1.10- 1.19 (m, 4 H) 0.46-0.98 (m, 12 H) 0.39-0.42 (m, 1 H)hLPA1 IC₅₀ = 22 nM. Example 5 (1S,3S)-3-((6-(5-((((cyclopentylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylicacid 110

LCMS, [M + H]⁺ = 447.4 ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (br. s., 1H),7.98 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.36-6.86 (m, 1H),6.03-5.43 (m, 2H), 4.77 (br. s., 1H), 3.26-2.57 (m, 6H), 2.19- 1.31 (m,8H), 1.07-0.65 (m, 1H), 0.62-−0.21 (m, 4H) hLPA1 IC₅₀ = 31 nM. Example 4(1S,3S)-3-((6-(5- ((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-(methyl-d3)-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 111

LCMS, [M + H]⁺ = 461.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (d, J = 2.4 Hz,1H), 7.98 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 6.3 Hz, 1H), 5.60 (br. s.,2H), 4.77 (br. s., 1H), 3.59 (br. s., 1H), 2.63 (br. s., 4H), 1.94 (br.s., 1H), 1.86-1.69 (m, 3H), 1.68- 1.25 (m, 12H) hLPA1 IC₅₀ = 23 nM.Example 4 (1S,3S)-3-((6-(5- (((cyclopentyl(methyl)earbamoyl)oxy)methyl)-1-(methyl-d3)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 112

LCMS, [M + H]⁺ = 449.4 ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (d, J = 2.3 Hz,1H), 7.98 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 5.83- 5.25 (m,2H), 4.77 (br. s., 1H), 3.29-2.97 (m, 2H), 2.85-2.59 (m, 4H), 1.94 (br.s., 1H), 1.88-1.71 (m, 3H), 1.68-1.33 (m, 5H), 1.31-1.14 (m, 2H),1.08-0.55 (m, 4H) hLPA1 IC₅₀ = 17 nM. Example 4 (1S,3S)-3-((6-(5-(((butyl(methyl)carbamoyl)oxy)methyl)- 1-(methyl-d3)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 113

LC/MS: [M + H]⁺ = 486.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.99-7.72 (m, 1H),7.48 (br d, J = 7.4 Hz, 1H), 5.62 (br s, 3H), 4.79 (br s, 1H), 4.10 (brs, 4H), 3.31-2.96 (m, 5H), 2.71-2.59 (m, 1H), 2.41 (br s, 3H), 1.97-1.77(m, 6H), 1.59-1.34 (m, 6H), 1.07-0.76 (m, 4H) hLPA1 IC₅₀ = 15 nM Example1 (1S,3S)-3-((6-(5- ((((cyclobutylmethyl)(ethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 114

LC/MS: [M + H]⁺ = 460.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (br d, J = 8.6Hz, 1H), 7.45 (br d, J = 8.7 Hz, 1H), 5.65 (s, 2H), 4.76 (br s, 1H),4.06 (s, 2H), 3.93-3.84 (m, 2H), 3.61-3.17 (m, 7H), 2.66-2.58 (m, 1H),2.39 (s, 3H), 2.12-1.29 (m, 8H) hLPA1 IC₅₀ = 643 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((morpholine-4-carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 115

LC/MS: [M + H]⁺ = 458.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.2Hz, 1H), 7.48 (br d, J = 7.7 Hz, 1H), 5.86-5.45 (m, 2H), 4.78 (br s,1H), 4.10 (s, 3H), 3.12-2.92 (m, 2H), 2.89-2.76 (m, 3H), 2.62 (br s,1H), 2.41 (s, 3H), 2.09-1.42 (m, 8H), 0.97-0.64 (m, 1H), 0.55-−0.10 (m,4H) hLPA1 IC50 = 18 nM Example 1 (1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylicacid 116

LC/MS: [M + H]⁺ = 460.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.03-7.74 (m, 1H),7.47 (br d, J = 7.7 Hz, 1H), 6.06-5.43 (m, 2H), 4.78 (br s, 1H), 4.10(s, 3H), 3.02 (br d, J = 6.8 Hz, 1H), 2.88 (br d, J = 6.9 Hz, 1H),2.81-2.69 (m, 3H), 2.62 (br t, J = 10.2 Hz, 1H), 2.41 (s, 3H), 2.12-1.42(m, 9H), 0.81 (br d, J = 6.1 Hz, 3H), 0.62 (br d, J = 5.8 Hz, 3H) hLPA1IC₅₀ = 29 nM Example 1 (1S,3S)-3-((6-(5-(((isobutyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 117

LC/MS: [M + H]⁺ = 502.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (br d, J = 6.1Hz, 1H), 7.48 (br d, J = 8.6 Hz, 1H), 5.73- 5.48 (m, 2H), 4.78 (br s,1H), 4.10 (br d, J = 7.7 Hz, 3H), 3.82 (br d, J = 8.8 Hz, 1H), 3.62 (brd, J = 12.5 Hz, 1H), 3.24 (br s, 1H), 3.17 (s, 1H), 3.09 (br d, J = 6.3Hz, 1H), 3.04-2.92 (m, 2H), 2.84-2.72 (m, 3H), 2.41 (s, 3H), 2.05-1.10(m, 13H) hLPA1 IC₅₀ = 17 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 118

LC/MS: [M + H]⁺ = 495.0 ¹H NMR (500 MHz, DMSO-d₆) δ 8.69-7.72 (m, 2H),7.72-7.03 (m, 4H), 5.79-5.58 (m, 2H), 4.78 (br s, 1H), 4.45 (s, 2H),4.27-3.82 (m, 2H), 3.17 (s, 1H), 2.97-2.75 (m, 3H), 2.63 (br s, 1H),2.44-2.29 (m, 3H), 2.02 (br d, J = 12.7 Hz, 1H), 1.93-1.40 (m, 7H) hLPA1IC₅₀ = 211 nM Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(pyridin-2- ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid119

LC/MS: [M + H]⁺ = 432.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.48 (br d, J = 8.6 Hz, 1H), 5.64 (br d, J = 13.1 Hz, 2H), 4.78 (brs, 1H), 4.09 (s, 3H), 3.31-3.04 (m, 2H), 2.84-2.70 (m, 3H), 2.62 (br s,1H), 2.41 (s, 3H), 2.01 (br d, J = 14.1 Hz, 1H), 1.92-1.72 (m, 3H),1.69-1.43 (m, 4H), 1.08- 0.78 (m, 3H) hLPA₁ IC₅₀ = 878 nM Example 1(1S,3S)-3-((6-(5- (((ethyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 120

LC/MS: [M + H]⁺ = 495.1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.64-8.27 (m, 2H),7.85 (d, J = 8.6 Hz, 1H), 7.70-7.31 (m, 2H), 6.59 (s, 1H), 5.81- 5.57(m, 2H), 4.79 (br s, 1H), 4.52-4.27 (m, 2H), 4.20-3.96 (m, 2H), 3.39 (brs, 1H), 2.98-2.70 (m, 3H), 2.63 (br d, J = 9.8 Hz, 1H), 2.38 (br d, J =17.8 Hz, 2H), 2.10- 1.96 (m, 1H), 1.91-1.04 (m, 8H) hLPA₁ IC₅₀ = 809 nMExample 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(pyridin-3-ylmethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 121

LC/MS: [M + H]+ = 496.1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (br d, J = 4.9Hz, 1H), 8.61 (d, J = 4.9 Hz, 1H), 7.95- 7.68 (m, 1H), 7.50-7.20 (m,2H), 5.85-5.44 (m, 2H), 4.77 (br s, 1H), 4.67- 4.49 (m, 2H), 4.13 (s,1H), 2.95-2.75 (m, 4H), 2.64 (br s 1H), 2.44- 2.33 (m, 4H), 2.09-1.97(m, 1H), 1.91-1.74 (m, 4H), 1.68-1.48 (m, 4H) hLPA1 IC₅₀ = 1087 nMExample 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(pyrimidin-2-ylmethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 122

LC/MS: [M + H]⁺ = 495.0 ¹H NMR (500 MHz, DMSO-d₆) δ 8.85-8.33 (m, 1H),8.06-7.72 (m, 1H), 7.58-7.39 (m, 2H), 7.37-6.99 (m, 2H), 6.04- 5.53 (m,2H), 4.87- 4.31 (m, 2H), 4.23-3.84 (m, 3H), 3.17 (s, 1H), 2.93-2.73 (m,3H), 2.67- 2.57 (m, 1H), 2.43- 2.29 (m, 3H), 2.02 (br d, J = 13.9 Hz,1H), 1.90- 1.73 (m, 2H), 1.66-1.47 (m, 2H), 1.37-1.14 (m, 2H), 1.00 (brd, J = 6.1 Hz, 1H), 0.85 (br d, Example 1 J = 6.3 Hz, 1H)(1S,3S)-3-((2-methyl-6-(1-methyl-5- hLPA1 IC₅₀ = 873 nM(((methyl(pyridin-4- ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid123

LC/MS: [M + H]⁺ = 496.1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.63-8.51 (m, 1H),8.47-8.30 (m, 1H), 7.96-7.59 (m, 1H), 7.56-7.27 (m, 1H), 6.05- 5.37 (m,2H), 4.77 (br s, 1H), 4.62-4.39 (m, 2H), 4.24-3.84 (m, 3H), 3.45 (br s,1H), 2.98-2.76 (m, 3H), 2.63 (br s, 1H), 2.41- 2.24 (m, 3H), 2.15- 1.35(m, 8H) hLPA1 IC₅₀ = 618 nM Example 1 (1S,3S)-3-((2-methyl-641-methyl-5-(((methyl(pyrazin-2-ylmethyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 124

LC/MS: [M + H]⁺ = 498.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.49 (d, J = 8.5 Hz, 1H), 7.41- 7.12 (m, 1H), 6.14 (br s, 1H), 5.70(br s, 2H), 5.13- 3.29 (m, 7H), 2.71 (br s, 3H), 2.59-2.55 (m, 2H), 2.39(s, 3H), 2.14-1.31 (m, 9H) hLPA1 IC₅₀ = 982 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 125

LC/MS: [M + H]⁺ = 504.0 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5Hz, 2H), 7.49 (br d, J = 8.5 Hz, 1H), 6.00- 5.25 (m, 3H), 4.75 (br s,2H), 4.10 (br s, 4H), 2.90- 2.72 (m, 3H), 2.41 (s, 4H), 2.14-1.31 (m,13H) hLPA1 IC₅₀ = 668 nM Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(morpholin-3- ylmethyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid126

LC/MS: [M + H]⁺ = 488.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.94 (br d, J = 8.9Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.48 (br d, J = 8.5 Hz, 1H), 6.52 (brd, J = 8.2 Hz, 1H), 5.65 (br s, 2H), 4.76 (br s, 1H), 4.09 (s, 3H),3.55- 2.96 (m, 3H), 2.85- 2.70 (m, 3H), 2.60-2.56 (m, 1H), 2.40 (s, 3H),2.33-2.23 (m, 1H), 2.03- 1.19 (m, 11H) hLPA1 IC₅₀ = 346 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl((tetrahydrofuran-3-yl)methyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 127

LC/MS: [M + H]⁺ = 474.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (br d, J = 8.5Hz, 1H), 7.44 (br d, J = 8.5 Hz, 1H), 5.58 (s, 2H), 4.75 (br s, 1H),4.08 (s, 3H), 3.23-2.91 (m, 4H), 2.60 (br s, 1H), 2.39 (s, 3H),2.05-1.93 (m, 1H), 1.89-1.71 (m, 3H), 1.33-1.37 (m, 4H), 1.25- 1.12 (m,4H), 1.06- 0.77 (m, 5H), 0.58 (br s, 2H) hLPA1 IC₅₀ = 33 nM Example 1(1S,3S)-3-((6-(5- (((butyl(ethyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 128

LC/MS: [M + H]⁺ = 460.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 5.61 (s, 2H), 4.78 (br s, 1H), 4.09(s, 3H), 3.42-3.33 (m, 1H), 3.23-2.96 (m, 4H), 2.62 (br t, J = 10.4 Hz,1H), 2.41 (s, 3H), 2.01 (br d, J = 13.7 Hz, 1H), 1.91-1.73 (m, 3H),1.68- 1.41 (m, 5H), 1.28 (br s, 1H), 1.00 (br d, J = 6.1 Hz, 1H),0.92-0.76 (m, 3H), 0.62 (br s, 1H) hLPA1 IC₅₀ = 158 nM Example 3(1S,3S)-3-((6-(5- (((ethyl(propyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 129

LCMS, [M + H]⁺ = 486 ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (br d, J = 8.2 Hz,1H), 7.46 (br d, J = 8.5 Hz, 1H), 5.60 (br s, 2H), 4.78 (br s, 1H),4.15-4.03 (m, 3H), 3.53 (br s, 1H), 2.80- 2.70 (m, 3H), 2.65-2.57 (m,1H), 2.41 (s, 3H), 2.05-1.96 (m, 1H), 1.89- 1.72 (m, 3H), 1.66- 1.46 (m,4H), 0.86-0.82 (m, 2H), 0.76-0.48 (m, 8H) hLPA1 IC₅₀ = 352 nM Example 3(1S,3S)-3-((6-(5-((((1- isopropylcyclopropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 130

LCMS, [M + H]⁺ = 500 ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J = 8.5 Hz,1H), 7.46 (br d, J = 8.5 Hz, 1H), 5.59 (br s, 2H), 4.77 (br s, 1H),4.15-4.02 (m, 3H), 3.59 (br s, 1H), 2.79- 2.66 (m, 3H), 2.63-2.56 (m,1H), 2.39 (s, 3H), 2.04-1.94 (m, 1H), 1.88- 1.71 (m, 3H), 1.66- 1.44 (m,4H), 1.15-1.08 (m, 1H), 0.90-0.85 (m, 2H), 0.83-0.32 (m, 9H) hLPA1 IC₅₀= 243 nM Example 10 (1S,3S)-3-((6-(5-((((1-isobutylcyclopropyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid131

LCMS, [M + H]⁺ = 472 ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (br d, J = 7.9 Hz,1H), 7.46 (br d, J = 8.2 Hz, 1H), 5.60 (s, 2H), 4.81-4.71 (m, 1H),4.15-4.01 (m, 3H), 3.66 (br s, 3H), 2.78-2.66 (m, 3H), 2.61-2.55 (m,1H), 2.40 (s, 3H), 2.02-1.93 (m, 1H), 1.85-1.73 (m, 3H), 1.64-1.44 (m,5H), 0.85-0.76 (m, 1H), 0.67- 0.57 (m, 4H), 0.44 (br s, 1H) hLPA1 IC₅₀ =187 nM Example 10 (1S,3S)-3-((6-(5-((((1-ethylcyclopropyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid132

LCMS, [M + H]⁺ = 500 ¹H NMR (500 MHz, DMSO-d₆) δ 8.01-7.78 (m, 1H), 7.49(br d, J = 4.6 Hz, 1H), 5.58 (br s, 2H), 4.78 (br s, 1H), 4.09 (br s,3H), 3.54-3.32 (m, 2H), 2.63-2.58 (m, 3H), 2.46-2.32 (m, 3H), 2.08- 1.97(m, 3H), 1.91- 1.74 (m, 4H), 1.70-1.47 (m, 8H), 1.28-1.19 (m, 1H),1.07-0.79 (m, 3H), 0.62-0.56 (m, 1H) hLPA1 IC₅₀ = 180 nM Example 10(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(1-propylcyclobutyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 133

LCMS, [M + H]⁺ = 486 ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (br d, J = 7.3 Hz,1H), 7.48 (br d, J = 8.5 Hz, 1H), 5.57 (br s, 2H), 4.82-4.73 (m, 1H),4.08 (s, 3H), 2.64- 2.57 (m, 3H), 2.41 (s, 3H), 2.23-1.74 (m, 9H),1.70-1.44 (m, 8H), 0.92- 0.41 (m, 3H) hLPA1 IC₅₀ = 174 nM Example 10(1S,3S)-3-((6-(5-((((1- ethylcyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 134

LCMS, [M + H]⁺ = 470 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.48 (d, J = 8.9 Hz, 1H), 5.62 (s, 2H), 4.77 (br s, 1H), 4.06 (s,3H), 3.90 (s, 1H), 3.81 (br s, 3H), 2.64-2.58 (m, 1H), 2.41 (s, 3H),2.10- 1.97 (m, 5H), 1.88-1.75 (m, 3H), 1.74-1.50 (m, 6H) hLPA1 IC₅₀ = 76nM Example 1 (1S,3S)-3-((6-(5-(((2- azaspiro[3.3]heptane-2-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 135

[M + H]⁺ = 484 ¹H NMR (500 MHz, DMSO-d₆) δ 7.79 (br d, J = 8.2 Hz, 1H),7.44 (br d, J = 8.5 Hz, 1H), 5.62- 5.56 (m, 2H), 4.74 (br s, 1H),4.08-4.04 (m, 2H), 3.86-3.61 (m, 2H), 3.18 (s, 3H), 3.04 (s, 1H), 2.62-2.56 (m, 1H), 2.38 (s, 3H), 2.01-1.92 (m, 1H), 1.90-1.71 (m, 10H),1.65-1.41 (m, 4H) hLPA1 IC₅₀ = 47 nM Example 1 (1S,3S)-3-((6-(5-(((6-azaspiro[3.4]octane-6- carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylicacid 136

LCMS, [M + H]⁺ = 458 ¹H NMR (500 MHz, CDCl₃) δ 7.98 (d, J = 8.5 Hz, 1H),7.25 (d, J = 8.8 Hz, 1H), 5.77 (s, 2H), 4.76-4.71 (m, 1H), 4.17- 4.13(m, 4H), 2.93- 2.82 (m, 3H), 2.53 (s, 3H), 2.07 (s, 10H), 1.68 (br s,5H) hLPA1 IC₅₀ = 36 nM Example 1 (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 137

LCMS, [M + H]⁺ = 586 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5 Hz,1H), 7.47 (br d, J = 8.9 Hz, 1H), 5.62 (br s, 2H), 4.77 (br s, 1H), 4.09(s, 3H), 3.30- 2.86 (m, 4H), 2.61-2.57 (m, 1H), 2.41 (s, 3H), 2.03-1.92(m, 1H), 1.88- 1.72 (m, 3H), 1.62 (br d, J = 9.2 Hz, 5H) 1.31- 1.19 (m,4H) 0.89-0.75 (m, 3H), 0.73-0.60 (m, 3H) hLPA1 IC₅₀ = 292 nM Example 1(1S,3S)-3-((6-(5-(((3,3- dimethylpiperidine-1-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 138

LCMS, [M + H]⁺ = 446 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.3 Hz,1H), 7.48 (br d, J = 8.6 Hz, 1H), 5.63 (br s, 2H), 4.79 (br s, 1H), 4.09(s, 3H), 3.91- 3.90 (m, 1H), 2.69-2.61 (m, 3H), 2.41 (s, 3H), 1.62 (brs, 9H), 1.03 (br s, 3H), 0.93 (br s, 3H) hLPA1 IC₅₀ = 98 nM Example 3(1S,3S)-3-((6-(5- (((isopropyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 139

LCMS, [M + H]⁺ = 494 ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J = 8.2 Hz,1H), 7.48 (d, J = 8.9 Hz, 1H), 5.66 (br s, 2H), 4.78 (br s, 1H), 4.10(s, 3H), 2.82-2.68 (m, 5H), 2.67-2.59 (m, 2H), 2.41 (s, 3H), 2.06-1.97(m, 1H), 1.94-1.71 (m, 3H) 3H), 1.68-1.42 (m, 4H), 1.24 (s, 2H) hLPA1IC₅₀ = 70 nM Example 10 (1S,3S)-3-((6-(5-((((3,3-difluorocyclobutyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid140

LCMS, [M + H]⁺ = 472 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5 Hz,1H), 7.47 (br d, J = 8.5 Hz, 1H), 5.65 (br d, J = 4.6 Hz, 2H), 4.78 (brs, 1H), 4.08 (br d, J = 4.6 Hz, 3H), 3.36- 3.21 (m, 1H), 3.02 (s, 1H),2.90 (s, 1H), 2.62 (br s, 1H), 2.41 (s, 3H), 2.06-1.96 (m, 1H), 1.80 (brs, 3H), 1.57 (br t, J = 7.2 Hz, 6H), 1.23 (s, 2H), 0.99 (s, 3H), 0.94(s, 3H) hLPA1 IC₅₀ 148 nM Example 1 (1S,3S)-3-((6-(5-(((3,3-dimethylpyrrolidine-1- carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylicacid 141

LCMS, [M + H]⁺ = 494 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.2 Hz,1H), 7.52 (d, J = 8.5 Hz, 1H), 5.65 (br s, 2H), 4.45-4.38 (m, 1H), 4.10(s, 3H), 2.79-2.74 (m, 4H), 2.70-2.62 (m, 1H), 2.49-2.40 (m, J = 11.7,11.7 Hz, 2H), 2.37-2.34 (m, 3H), 2.30- 2.20 (m, 1H), 2.11- 2.00 (m, 1H),1.90-1.78 (m, 2H), 1.47-1.23 (m, 6H) hLPA1 IC₅₀ = 283 nM Example 10(1R,3S)-3-(((6-(5-((((3,3-difluoro- cyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid; cis isomer from epimerization in finalester hydrolysis 142

LCMS, [M + H]⁺ = 444 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5 Hz,1H), 7.47 (br d, J = 8.2 Hz, 1H), 5.65 (s, 2H), 4.81-4.73 (m, 1H), 4.10(s, 3H), 3.72-3.52 (m, 1H), 2.74 (br s, 3H), 2.65-2.57 (m, 1H), 2.41 (s,3H), 2.04-1.94 (m, 1H), 1.92-1.70 (m, 3H), 1.68-1.41 (m, 4H), 0.57 (brs, 2H), 0.48 (br s, 2H) hLPA1 IC₅₀ = 252 nM Example 10 (1S,3S)-3-((6-(5-(((cyclopropyl(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 143

LCMS, [M + H]⁺ = 480 ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J = 7.6 Hz,1H), 7.49 (br d, J = 7.6 Hz, 1H), 5.70 (s, 2H), 4.75 (br s, 1H), 4.09(s, 3H), 3.73-3.54 (m, 1H), 2.42-2.38 (m, 3H), 2.38-2.31 (m, 2H), 1.99-1.46 (m, 8H), 1.23 (s, 2H) hLPA1 IC₅₀ = 518 nM Example 1(1S,3S)-3-((6-(5-(((3,3-difluoro- pyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 144

LCMS, [M + H]⁺ = 470 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.4 Hz,1H), 7.47 (d, J = 8.6 Hz, 1H), 5.67 (s, 2H), 4.77 (br s, 1H), 4.09 (brs, 3H), 2.72-2.60 (m, 1H), 2.43 (s, 3H), 2.08- 1.97 (m, 1H), 1.83 (br d,J = 10.9 Hz, 3H), 1.75- 1.45 (m, 7H), 1.25 (s, 2H), 0.63-0.44 (m, 4H)hLPA1 IC₅₀ = 89 nM Example 1 (1S,3S)-3-((6-(5-(((5-azaspiro[2.4]heptane-5- carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylicacid 145

LCMS, [M + H]⁺ = 508 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.5 Hz,1H), 7.46 (d, J = 8.7 Hz, 1H), 5.65 (br s, 2H), 4.77 (br s, 1H), 4.10(s, 3H), 2.79 (br s, 3H), 2.70-2.62 (m, 1H), 2.43 (s, 3H), 2.39-2.19 (m,4H), 2.09-1.97 (m, 2H), 1.92-1.76 (m, 3H), 1.71- 1.60 (m, 2H), 1.59-1.47 (m, 2H), 1.25 (s, 2H) hLPA1 IC₅₀ = 94 nM Example 3(1S,3S)-3-((6-(5-(((((3,3-difluoro- cyclobutyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 146

LCMS, [M + H]⁺ = 484 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.2 Hz,1H), 7.51 (d, J = 8.5 Hz, 1H), 5.98- 5.48 (m, 2H), 4.45-4.36 (m, 1H),4.13 (s, 3H), 3.53-3.14 (m, 1H), 2.72 (s, 2H), 2.47-2.39 (m, 1H), 2.35(s, 3H), 2.27- 2.20 (m, 1H), 2.08-1.99 (m, 1H), 1.93-1.58 (m, 7H),1.50-1.20 (m, 6H), 0.75-0.65 (m, 1H), 0.58- 0.50 (m, 1H) hLPA1 IC₅₀ =1816 nM Example 3 (1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(spiro[2.3]hexan-1- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid (cis isomerfrom epimerization in final ester hydrolysis) 147

LCMS, [M + H]⁺ = 458 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.6 Hz,1H), 7.47 (d, J = 8.7 Hz, 1H), 5.65 (s, 2H), 4.81-4.74 (m, 1H), 4.08 (s,3H), 3.82-3.59 (m, 1H), 3.45-3.10 (m, 3H), 2.81-2.66 (m, 1H), 2.65-2.58(m, 1H), 2.41 (s, 3H), 2.08-1.95 (m, 1H), 1.93-1.73 (m, 4H), 1.67-1.33(m, 5H), 1.26- 1.18 (m, 1H), 0.99- 0.86 (m, 3H) hLPA1 IC₅₀ = 250 nMExample 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5- (((3-methylpyrrolidine-1-carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 148

LCMS, [M + H]⁺ = 470 ¹H NMR (500 MHz, DMSO-d₆) δ 7.85-7.78 (m, 1H), 7.46(d, J = 8.7 Hz, 1H), 5.67-5.54 (m, 4.77 (br s, 1H), 4.13- 4.03 (m, 3H),3.98- 3.85 (m, 1H), 3.77-3.66 (m, 1H), 3.20-3.05 (m, 1H), 2.93-2.77 (m,1H), 2.66-2.57 (m, 1H), 2.48- 2.42 (m, 1H), 2.40 (s, 3H), 2.04-1.96 (m,1H), 1.88-1.72 (m, 3H), 1.65- 1.52 (m, 4H), 1.50- 1.44 (m, 2H),1.37-1.24 (m, 3H) Example 1 hLPA1 IC₅₀ = 325 nM (1S,3S)-3-((6-(5-(((-2-azabicyclo[2.2.1]heptane-2- carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylicacid (mixture of diastereomers) 149

LCMS, [M + H]⁺ = 484 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5 Hz,1H), 7.47 (br d, J = 8.5 Hz, 1H), 5.68- 5.57 (m, 2H), 4.78 (br s, 1H),4.13-4.06 (m, 3H), 4.04-3.86 (m, 1H), 3.58- 3.47 (m, 3H), 2.68- 2.57 (m,2H), 2.41 (s, 3H), 2.05-1.96 (m, 1H), 1.89-1.74 (m, 4H), 1.69- 1.59 (m,3H), 1.54- 1.45 (m, 4H), 1.26-1.22 (m, 2H) hLPA1 IC₅₀ = 180 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((octahydrocyclopenta[b]pyrrole-1-carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 150

LCMS, [M + H]⁺ = 498 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.2 Hz,1H), 7.48 (br d, J = 8.5 Hz, 1H), 5.66 (br s, 2H), 4.82-4.75 (m, 1H),4.09 (s, 3H), 3.63- 3.33 (m, 1H), 3.32-3.08 (m, 2H), 2.97-2.72 (m, 1H),2.68-2.60 (m, 1H), 2.42 (s, 3H), 2.20-2.08 (m, 1H), 2.07-1.98 (m, 1H),1.98-1.90 (m, 1H), 1.90-1.73 (m, 3H), 1.68- 1.38 (m, 5H), 1.29- 1.11 (m,2H), 0.70-0.54 (m, 1H), 0.42-0.30 (m, Example 1 2H), 0.04-−0.11 (m, 2H)hLPA1 IC₅₀ = 91 nM (1S,3S)-3-((6-(5-(((3-(cyclopropylmethyl)pyrrolidine-1- carbonyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylicacid (mixture of diastereomers) 151

LCMS, [M + H]⁺ = 500 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.2 Hz,1H), 7.47 (br d, J = 8.3 Hz, 1H), 5.66 (br s, 2H), 4.80-4.74 (m, 1H),4.10 (s, 3H), 3.64- 3.33 (m, 1H), 2.86-2.77 (m, 1H), 2.74-2.64 (m, 1H),2.43 (s, 3H), 2.16- 2.08 (m, 1H), 2.08-2.00 (m, 1H), 1.98-1.77 (m, 5H),1.71-1.32 (m, 7H), 1.29-1.12 (m, 2H), 0.92- 0.81 (m, 6H) hLPA1 IC₅₀ =101 nM Example 1 (1S,3S)-3-((6-(5-(((3- isobutylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 152

LCMS, [M + H]⁺ = 471 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br s, 1H), 7.48(br d, J = 8.5 Hz, 1H), 5.64 (br s, 2H), 4.79 (br s, 1H), 4.09 (br s,3H), 3.61-3.12 (m, 3H), 2.67-2.59 (m, 1H), 2.42 (s, 3H), 2.06-1.94 (m,1H), 1.92-1.42 (m, 12H), 0.86-0.75 (m, 2H), 0.64-0.54 (m, 1H) hLPA1 IC₅₀= 157 M Example 1 (1S,3S)-3-((6-(5-(((2- ethylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 153

LCMS, [M + H]⁺ = 500 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.5 Hz,1H), 7.48 (br d, J = 7.3 Hz, 1H), 5.74- 5.48 (m, 2H), 4.78 (br s, 1H),4.10 (br s, 3H), 3.66- 3.11 (m, 3H), 2.41 (br s, 3H), 2.09-1.41 (m,14H), 1.36-1.07 (m, 2H), 0.89 (br s, 3H), 0.59- 0.42 (m, 3H) hLPA1 IC₅₀= 163 nM Example 1 (1S,3S)-3-((6-(5-(((2- isobutylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 154

LCMS, [M + H]⁺ = 511 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.2 Hz,1H), 7.55 (br d, J = 8.5 Hz, 1H), 5.82- 5.65 (m, 2H), 4.78-4.68 (m, 1H),4.10 (br s, 3H), 3.29-3.13 (m, 3H), 2.39 (s, 2H), 2.14-2.00 (m, 1H),1.98-1.46 (m, 12H) hLPA1 IC₅₀ = 321 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((2-(trifluoromethyl)pyrrolidine-1-carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 155

LCMS, [M + H]⁺ = 458 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.2 Hz,1H), 7.49 (d, J = 8.9 Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H), 4.07 (s,3H), 3.64-3.45 (m, 1H), 3.32-3.09 (m, 1H), 2.70-2.59 (m, 1H), 2.43 (s,3H), 2.30-2.15 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.73 (m, 3H), 1.67- 1.45(m, 4H), 1.16 (s,6H) hLPA1 IC₅₀ = 175 nM Example 1(1S,3S)-3-((6-(5-(((3,3- dimethylazetidine-1-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 156

LCMS, [M + H]⁺ = 444 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.5 Hz,1H), 7.48 (br d, J = 8.9 Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H), 4.07(s, 3H), 4.00-3.92 (m, 2H), 3.31-3.09 (m, 1H), 2.68-2.58 (m, 2H), 2.43(s, 3H), 2.02 (br d, J = 13.4 Hz, 1H), 1.94- 1.73 (m, 3H), 1.63 (br d, J= 10.1 Hz, 4H), 1.12 (d, J = 6.7 Hz, 3H) hLPA1 IC₅₀ = 231 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((3-methylazetidine-1-carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 157

LCMS, [M + H]⁺ = 444 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.5 Hz,1H), 7.48 (d, J = 8.9 Hz, 1H), 5.63 (s, 2H), 4.79 (br s, 1H), 4.08 (s,3H), 3.81-3.69 (m, 2H), 3.64-3.50 (m, 1H), 3.31-3.10 (m, 1H), 2.67- 2.59(m, 1H), 2.43 (s, 3H), 2.33-2.21 (m, 1H), 2.12-1.96 (m, 1H), 1.64 (br s,7H), 1.00 (d, J = 6.1 Hz, 3H) hLPA1 IC₅₀ = 529 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((2-methylazetidine-1-carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridine-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 158

LCMS, [M + H]⁺ = 498 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.2 Hz,1H), 7.48 (d, J = 8.5 Hz, 1H), 5.62 (br s, 2H), 4.78 (br s, 1H), 4.09(s, 3H), 3.32-3.12 (m, 1H), 2.74-2.58 (m, 4H), 2.41 (s, 3H), 2.10-1.70(m, 14H), 1.68-1.44 (m, 4H) hLPA1 IC₅₀ = 32 nM Example 10(1R,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(spiro[3.3]heptan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 159

LCMS, [M + H]⁺ = 484 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5 Hz,1H), 7.48 (d, J = 8.5 Hz, 1H), 5.64 (s, 2H), 4.78 (br s, 1H), 4.07 (s,3H), 3.69 (br s, 3H), 3.63-3.51 (m, 1H), 3.31- 3.11 (m, 2H), 2.42 (s,3H), 1.91-1.77 (m, 3H), 1.71-1.58 (m, 6H), 1.57- 1.47 (m, 6H) hLPA1 IC₅₀= 162 nM Example 1 (1S,3S)-3-((6-(5-(((2- azaspiro[3.4]octane-2-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 160

LCMS, [M + H]⁺ = 486 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.53 (d, J = 8.5 Hz, 1H), 5.63 (br s, 2H), 4.49-4.36 (m, 1H), 4.10(s, 3H), 2.77-2.69 (m, 3H), 2.48-2.39 (m, 1H), 2.37 (s, 3H), 2.31- 2.23(m, 1H), 2.12-2.02 (m, 1H) 1.92-1.59 (m, 6H), 1.50-1.20 (m, 4H),1.14-0.95 (m, 6H) hLPA1 IC₅₀ = 61 nM Example 3 (1R,3S)-3-((6-(5-((((3,3-dimethylcyclobutyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid(cis isomer from epimerization in final ester hydrolysis step) 161

LCMS, [M + H]⁺ = 472 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.5 Hz,1H), 7.46 (d, J = 8.7 Hz, 1H), 5.65 (s, 2H), 4.77 (br s, 1H), 4.09 (s,3H), 3.81-3.66 (m, 1H), 2.82-2.70 (m, 1H), 2.69-2.62 (m, 1H), 2.43 (s,3H), 2.06-1.97 (m, 1H), 1.92-1.76 (m, 3H), 1.66 (br s, 6H), 1.46- 1.18(m, 3H), 1.03 (s, 2H), 0.86-0.71 (m, 3H) hLPA1 IC₅₀ = 178 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((3-methylpiperidine-1-carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 162

LCMS, [M + H]⁺ = 472 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.6 Hz,1H), 7.45 (d, J = 8.6 Hz, 1H), 5.63 (s, 2H), 4.82-4.71 (m, 1H), 4.09 (s,3H), 3.62-3.53 (m, 2H), 3.34-3.18 (m, 1H), 2.79 (br s, 3H), 2.70- 2.61(m, 1H), 2.42 (s, 3H), 2.07-1.97 (m, 1H), 1.89-1.77 (m, 3H), 1.70- 1.47(m, 4H), 1.31- 1.15 (m, 2H), 0.42-0.16 (m, 2H), 0.03-−0.26 (m, 2H) hLPA1IC₅₀ = 34 nM Example 1 (1S,3S)-3-((6-(5-((((2-cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid163

LCMS, [M + H]⁺ = 486 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.5 Hz,1H), 7.48 (d, J = 8.5 Hz, 1H), 5.66 (br d, J = 9.5 Hz, 2H), 4.83- 4.75(m, 1H), 4.10 (s, 3H), 3.18 (br s, 1H), 2.93- 2.81 (m, 1H), 2.74 (s,1H), 2.68-2.60 (m, 1H), 2.42 (s, 3H), 2.07-1.98 (m, 1H), 1.94-1.73 (m,6H), 1.67-1.34 (m, 6H), 0.93-0.75 (m, 6H) hLPA1 IC₅₀ = 104 nM Example 1(1S,3S)-3-((6-(5-(((3- isopropylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 164

LCMS, [M + H]⁺ = 484 ¹H NMIR (500 MHz, DMSO-d₆) δ 7.82 (br d, J = 8.5Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 5.65 (br s, 2H), 4.80-4.74 (m, 1H),4.08 (s, 3H), 3.33-3.08 (m, 2H), 2.88 (s, 2H), 2.65-2.58 (m, 1H), 2.40(s, 3H), 2.04-1.95 (m, 1H), 1.90 (s, 4H), 1.62 (br s, 6H), 0.71-0.54 (m,1H), 0.42-0.26 (m, 2H), 0.16-0.02 (m, 2H) hLPA1 IC₅₀ = 83 nM Example 1(1S,3S)-3-((6-(5-(((3- cyclopropylpyrrolidine-1-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 165

LCMS, [M + H]⁺ = 472 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.49 (d, J = 8.9 Hz, 1H), 5.67 (br s, 2H), 4.83-4.76 (m, 1H), 4.10(s, 3H), 3.24-3.09 (m, 1H), 2.98-2.78 (m, 1H), 2.77-2.69 (m, 1H),2.67-2.61 (m, 1H), 2.42 (s, 3H), 2.06-1.79 (m, 6H), 1.67-1.23 (m, 8H),0.93-0.79 (m, 3H) hLPA1 IC₅₀ 102 nM Example 1 (1S,3S)-3-((6-(5-(((3-ethylpyrrolidine-l-carbonyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid(mixture of diastereomers) 166

LCMS, [M + H]⁺ = 486 ¹H NMIR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.48 (d, J = 8.5 Hz, 1H), 5.66 (br s, 2H), 4.82-4.74 (m, 1H), 4.09(s, 3H), 3.24-3.07 (m, 1H), 2.90 (s, 1H), 2.76-2.67 (m, 1H), 2.67- 2.60(m, 1H), 2.42 (s, 3H), 2.10-1.97 (m, 2H), 1.92 (s, 5H), 1.68-1.34 (m,5H), 1.32- 1.19 (m, 4H), 0.92-0.80 (m, 3H) hLPA1 IC₅₀ = 109 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((3-propylpyrrolidine-1-carbonyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 167

LCMS, [M + H]⁺ = 470 ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J = 8.5 Hz,1H), 7.50 (d, J = 8.5 Hz, 1H), 5.64 (s, 2H), 4.79 (br s, 1H), 4.09 (s,3H), 3.31-3.13 (m, 1H), 2.67-2.59 (m, 1H), 2.42 (s, 3H), 2.06-1.98 (m,1H), 1.91-1.74 (m, 3H), 1.67-1.46 (m, 8H), 1.39-1.33 (m, 4H) hLPA1 IC₅₀= 317 nM Example 1 (1S,3S)-3-((6-(5-(((-7-azabicyclo[2.2.1]heptane-7-carbonyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 168

LCMS, [M + H]⁺ = 486 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.48 (d, J = 8.5 Hz, 1H), 5.63 (br s, 2H), 4.78 (br s, 1H), 4.10(s, 3H), 2.72 (br s, 3H), 2.68-2.58 (m, 1H), 2.41 (s, 3H), 2.00 (br s,1H), 1.93-1.71 (m, 6H), 1.64 (br s, 5H), 1.07-0.95 (m, 6H) hLPA1 IC₅₀ =29 nM Example 3 (1S,3S)-3-((6-(5-((((3,3-dimethyl-cyclobutyl)(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 169

LCMS, [M + H]⁺ = 520 ¹H NMR (500 MHz, DMSO-d₆) δ 7.91-7.81 (m, 1H),7.52-7.45 (m, 1H), 7.37-7.19 (m, 5H), 5.72 (br s, 2H), 4.83- 4.75 (m,1H), 4.11 (br d, J = 13.7 Hz, 3H), 3.81- 3.63 (m, 1H), 3.39-3.10 (m,3H), 2.67-2.61 (m, 1H), 2.43 (br d, J = 4.9 Hz, 3H), 2.24-2.16 (m, 1H),2.07-1.99 (m, 1H), 1.97-1.73 (m, 4H), 1.70- 1.47 (m, 4H) hLPA1 IC₅₀ =336 nM Example 1 (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((3-phenylpyrrolidine-1-carbonyl) oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid (mixture ofdiastereomers) 170

LCMS, [M + H]⁺ = 460 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.5 Hz,1H), 7.48 (br d, J = 8.5 Hz, 1H), 5.60 (s, 2H), 4.79 (br s, 1H), 4.10(s, 3H), 2.77 (s, 3H), 2.68- 2.58 (m, 1H), 2.42 (s, 3H), 2.09-1.97 (m,1H), 1.93-1.73 (m, 3H), 1.69- 1.43 (m, 4H), 1.27 (s, 9H) hLPA1 IC₅₀ =183 nM Example 1 (1S,3S)-3-((6-(5-(((tert-butyl(methyl)carbamoyl)oxy)methyl)-1- methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 171

LCMS, [M + H]⁺ = 484 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.48 (d, J = 8.5 Hz, 1H), 5.66 (s, 2H), 4.79 (br s, 1H), 4.09 (s,3H), 3.59-3.16 (m, 2H), 2.69-2.60 (m, 1H), 2.42 (s, 3H), 2.06-1.95 (m,1H), 1.91-1.71 (m, 3H), 1.68-1.44 (m, 4H), 1.31-1.11 (m, 4H), 0.28 (s,4H) hLPA1 IC₅₀ = 162 nM Example 1 (1S,3S)-3-((6-(5-(((6-azaspiro[2.5]octane-6-carbonyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 172

LCMS, [M + H]⁺ = 472 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.53 (d, J = 8.5 Hz, 1H), 5.68- 5.59 (m, 2H), 5.16-4.91 (m, 1H),4.47-4.36 (m, 1H), 4.09 (s, 3H), 3.87- 3.60 (m, 2H), 2.80-2.64 (m, 3H),2.45-2.39 (m, 1H), 2.37 (s, 3H), 2.30- 2.22 (m, 1H), 2.09-2.02 (m, 1H),1.93-1.78 (m, 3H), 1.72-1.49 (m, 4H), 1.47-1.28 (m, 5H) hLPA1 IC₅₀ = 312nM Example 3 (1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(3-methylbut-2-en-1- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid (cis isomerfrom epimerization during final hydrolysis step) 173

LCMS, [M + H]⁺ = 432 ¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (d, J = 2.4 Hz,1H), 7.99 (br d, J = 8.2 Hz, 1H), 7.58- 7.52 (m, 1H), 5.67-5.58 (m, 2H),4.79 (br s, 1H), 4.10 (s, 3H), 3.20-3.01 (m, 2H), 2.77 (br d, J = 15.9Hz, 3H), 2.71- 2.62 (m, 1H), 2.00-1.72 (m, 4H), 1.72-1.41 (m, 5H),1.40-1.28 (m, 1H), 0.86-0.61 (m, 3H) hLPA1 IC₅₀ = 131 nM Example 1(1S,3S)-346-(1-methyl-5- (((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylicacid 174

LCMS, [M + H]⁺ = 444 ¹H NMIR (500 MHz, DMSO-d₆) δ 8.35 (d, J = 2.4 Hz,1H), 8.00 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.9, 2.7 Hz, 1H), 5.63 (s,2H), 4.79 (br s, 1H), 4.57-4.17 (m, 1H), 4.10 (s, 3H), 2.80-2.63 (m,4H), 2.12-1.94 (m, 4H), 1.90-1.74 (m, 4H), 1.72- 1.48 (m, 5H) hLPA1 IC₅₀= 58 nM Example 1 (1S,3S)-3-((6-(5- (((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 175

LCMS, [M + H]⁺ = 470 ¹H NMR (500 MHz, DMSO-d₆) δ 8.43-8.26 (m, 1H),8.08-7.91 (m, 1H), 7.64-7.44 (m, 1H), 5.63 (br s, 2H), 4.78 (br s, 1H),4.08 (br s, 3H), 3.30-3.11 (m, 3H), 2.71- 2.60 (m, 1H), 2.00- 1.88 (m,2H), 1.88-1.73 (m, 9H), 1.70-1.44 (m, 4H) hLPA1 IC₅₀ = 703 nM Example 1(1S,3S)-3-((6-(5-(((6- azaspiro[3.4]octane-6-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 176

LCMS, [M + H]⁺ = 456 ¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (d, J = 2.4 Hz,1H), 8.00 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.7, 2.6 Hz, 1H), 5.60 (s,2H), 4.79 (br s, 1H), 4.08 (s, 3H), 3.84 (s, 4H), 2.72-2.63 (m, 1H),2.13- 2.02 (m, 4H), 2.01- 1.92 (m, 1H), 1.90-1.76 (m, 3H), 1.76-1.60 (m,4H), 1.60- 1.48 (m, 2H) hLPA1 IC₅₀ = 400 nM Example 1(1S,3S)-3-((6-(5-(((2- azaspiro[3.3]heptane-2-carbonyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 177

LCMS, [M + H]⁺ = 472 ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J = 8.5 Hz,1H), 7.49 (d, J = 8.5 Hz, 1H), 5.69- 5.61 (m, 2H), 5.17-4.91 (m, 1H),4.78 (br s, 1H), 4.09 (s, 3H), 3.85-3.61 (m, 2H), 2.80-2.66 (m, 3H),2.65-2.59 (m, 1H), 2.41 (s, 3H), 2.06-1.96 (m, 1H), 1.90-1.74 (m, 3H),1.73-1.60 (m, 4H), 1.59-1.47 (m, 4H), 1.46- 1.37 (m, 2H) hLPA1 IC₅₀ = 21nM Example 3 (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(3-methylbut-2-en-1- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 178

LCMS, [M + H]⁺ = 478 ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J = 8.5 Hz,1H), 7.49 (d, J = 8.5 Hz, 1H), 5.62 (s, 2H), 4.81-4.74 (m, 1H), 4.57 (s,1H), 4.47 (s, 1H), 4.11 (s, 3H), 2.82 (s, 3H), 2.65-2.58 (m, 1H), 2.42(s, 3H), 2.05-1.96 (m, 1H), 1.89-1.74 (m, 3H), 1.64 (br s, 4H), 1.28 (brs, 6H) hLPA1 IC₅₀ = 156 nM Example 3 (1S,3S)-3-((6-(5-((((1-fluoro-2-methylpropan-2-yl)(methyl) carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl- pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 179

[M + H]⁺ = 484 ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J = 8.5 Hz, 1H),7.45 (d, J = 8.6 Hz, 1H), 5.63 (s, 2H), 4.75 (br s, 1H), 4.09 (s, 3H),2.88-2.72 (m, 3H), 2.70-2.59 (m, 1H), 2.41 (s, 3H), 2.38-2.28 (m, 2H),2.08-1.75 (m, 7H), 1.70-1.45 (m, 4H), 0.47-0.26 (m, 4H) hLPA1 IC₅₀ = 14nM Example 3 (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(spiro[2.3]hexan-5- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic acid 180

LCMS, [M + H]⁺ = 484 ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (br s, 1H), 7.99(br d, J = 8.9 Hz, 1H), 7.59-7.51 (m, 1H), 5.60 (br s, 2H), 4.82- 4.74(m, 1H), 4.09 (s, 3H), 2.72-2.61 (m, 4H), 2.05-1.70 (m, 15H), 1.70-1.60(m, 2H), 1.60- 1.44 (m, 2H) hLPA1 IC₅₀ = 62 nM Example 10(1S,3S)-346-(1-methyl-5- (((methyl(spiro[3.3]heptan-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 181

[M + H]⁺ = 472 ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (br d, J = 2.1 Hz, 1H),7.98 (br d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.9, 2.7 Hz, 1H), 5.60 (br s,2H), 4.78 (br s, 1H), 4.61-4.23 (m, 1H), 4.10 (s, 3H), 2.71 (s, 3H),2.68-2.61 (m, 1H), 2.08-1.71 (m, 7H), 1.66 (br d, J = 8.9 Hz, 2H),1.60-1.46 (m, 2H), 1.14- 0.90 (m, 6H) hLPA1 IC₅₀ = 101 nM Example 10(1S,3S)-3-((6-(5-((((3,3- dimethylcyclobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 182

LCMS, [M + H]⁺ = 476 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.46 (d, J = 8.6 Hz, 1H), 5.63 (s, 2H), 5.17-4.99 (m, 1H),4.79-4.71 (m, 1H), 4.09 (s, 3H), 3.69-3.51 (m, 1H), 3.46 (br s, 1H),2.75 (s, 3H), 2.67-2.57 (m, 1H), 2.41 (s, 4H), 2.32- 2.17 (m, 2H),2.03-1.95 (m, 1H), 1.88-1.75 (m, 3H), 1.69-1.45 (m, 4H) hLPA1 IC₅₀ = 61nM Example 10 (1S,3S)-3-((6-(5-((((3-fluorocyclobutyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid(mixture of diastereomers) 183

LCMS, [M + H]⁺ = 470 ¹H NMR (500 MHz, CHLOROFORM-d) δ 8.34 (d, J = 2.5Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.8, 2.8 Hz, 1H), 5.76(s, 2H), 4.79- 4.69 (m, 1H), 4.16 (s, 3H), 3.01-2.82 (m, 4H), 2.47-2.32(m, 2H), 2.18- 1.87 (m, 7H), 1.85- 1.56 (m, 4H), 0.61-0.27 (m, 4H) hLPA1IC₅₀ = 20 nM Example 3 (1S,3S)-3-((6-(1-methyl-5-(((methyl(spiro[2.3]hexan-5- yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 184

LCMS, [M + H]⁺ = 486 ¹H NMR (500 MHz, DMSO-d₆) δ 7.94-7.76 (m, 1H),7.55-7.40 (m, 1H), 5.75-5.53 (m, 2H), 4.77 (br s, 1H), 4.09 (s, 3H),3.30-3.02 (m, 1H), 2.90-2.72 (m, 3H), 2.70- 2.58 (m, 1H), 2.45- 2.32 (m,3H), 2.06-1.94 (m, 1H), 1.90-1.72 (m, 3H), 1.67-1.43 (m, 4H), 1.08-0.93(m, 3H), 0.92- 0.77 (m, 3H), 0.75- 0.49 (m, 1H), 0.46-0.14 (m, 1H), 0.14to −0.15 (m, 1H) Example 3 hLPA1 IC₅₀ = 37 nM (1S,3S)-3-((6-(5-(((((2,2- dimethylcyclopropyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid (mixture ofdiastereomers) 185

LCMS, [M + H]⁺ = 472 ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (br s, 1H), 7.99(br d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.6, 2.5 Hz, 1H), 5.63 (s, 2H),4.84-4.73 (m, 1H), 4.11 (s, 3H), 2.82 (br s, 3H), 2.73-2.63 (m, 1H),2.03- 1.93 (m, 1H), 1.91- 1.74 (m, 3H), 1.72-1.49 (m, 4H), 1.26 (s, 1H),0.97 (br s, 6H), 0.66 (br s, 1H), 0.38 (br s, 1H), 0.02 (br s, 1H) hLPA1IC₅₀ = 86 nM Example 3 (1S,3S)-3-((6-(5-(((((2,2-dimethylcyclopropyl)methyl)(methyl) carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid(mixture of diastereomers) 186

LCMS, [M + H]⁺ = 480 ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (d, J = 2.3 Hz,1H), 7.99 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.7, 2.7 Hz, 1H), 5.64 (brs, 2H), 4.82-4.73 (m, 1H), 4.10 (s, 3H), 2.83 (br s, 3H), 2.72-2.64 (m,1H), 2.01-1.93 (m, 1H), 1.90-1.73 (m, 4H), 1.71- 1.48 (m, 5H), 1.25 (s,1H), 1.23-1.09 (m, 1H) hLPA1 IC₅₀ = 67 nM Example 3(1S,3S)-3-((6-(5-(((((2,2- difluorocyclopropyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (mixture of diastereomers) 187

LCMS, [M + H]⁺ = 492 ¹H NMR (500 MHz, DMSO-d₆) δ 7.90-7.73 (m, 1H),7.51-7.42 (m, 1H), 5.64-5.58 (m, 2H), 4.76 (br s, 1H), 4.08 (br s, 3H),3.81-3.74 (m, 2H), 3.31-3.22 (m, 1H), 3.15-3.09 (m, 1H), 2.66- 2.57 (m,1H), 2.38 (br s, 3H), 1.98-1.72 (m, 5H), 1.67-1.39 (m, 6H), 1.32- 1.24(m, 3H), 1.09- 1.01 (m, 3H) hLPA1 IC₅₀ = 50 nM Example 3(1S,3S)-3-(6-(5-((((3-fluoro-3- methylbutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 188

LCMS, [M + H]⁺ = 478 ¹H NMR (500 MHz, DMSO-d₆) δ 8.39-8.25 (m, 1H),8.08-7.93 (m, 1H), 7.54 (br s, 1H), 5.66- 5.53 (m, 2H), 4.76 (br s, 1H),4.09 (br s, 2H), 3.86- 3.74 (m, 2H), 3.31- 3.24 (m, 1H), 3.16-3.12 (m,1H), 2.68-2.60 (m, 1H), 1.97-1.73 (m, 5H), 1.63 (br s, 6H), 1.33- 1.25(m, 3H), 1.14-1.07 (m, 3H) hLPA1 IC₅₀ = 32 nM Example 3 (1S,3S)-3-((6-(5-((((3-fluoro-3- methylbutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 189

LCMS, [M + H]⁺ = 490 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.4 Hz,1H), 7.46 (br d, J = 8.6 Hz, 1H), 5.69 (s, 2H), 4.77 (br s, 1H), 4.11(s, 3H), 3.72-3.23 (m, 1H), 2.85 (br s, 3H), 2.72- 2.60 (m, 1H), 2.42(s, 3H), 2.20-1.73 (m, 9H), 1.65 (br d, J = 9.8 Hz, 5H) hLPA1 IC₅₀ = 120nM Example 3 (1S,3S)-3-((6-(5-(((((1- fluorocyclobutyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylicacid 190

LCMS, [M + H]⁺ = 464.1 ¹H NMR (500 MHz, CDCl₃) δ 8.12 (d, J = 8.8 Hz,1H), 7.86 (br t, J = 7.8 Hz, 1H), 5.64-5.57 (m, 1H), 5.55-5.47 (m, 1H),4.86 (br s, 1H), 4.53 (dt, J = 10.4, 5.4 Hz, 1H), 4.43 (dt, J = 10.5,5.3 Hz, 1H), 4.22 (s, 3H), 3.45 (q, J = 7.1 Hz, 2H), 2.97 (d, J = 12.9Hz, 3H), 2.88 (br s, 1H), 2.74 (d, J = 2.2 Hz, 3H), 2.18-1.76 (m, 9H),1.68 (br d, J = 6.3 Hz, 1H) ¹⁹F-NMR: −221.9 ppm hLPA1 IC₅₀ = 81 nM(1S,3S)-3-((6-(5-((((3- fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-2-methylpyridin-3-yl)oxy)cyclohexane-l-carboxylic acid 191

LCMS, [M + H]⁺ = 464.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.48 (d, J = 8.7 Hz, 1H), 7.33 (br t, J = 5.6 Hz, 1H), 5.64 (s,2H), 4.79 (br s, 1H), 4.47 (t, J = 6.1 Hz, 1H), 4.37 (t, J = 6.0 Hz,1H), 4.08 (s, 3H), 3.02 (q, J = 6.0 Hz, 2H), 2.71-2.59 (m, 1H), 2.42 (s,3H), 2.11-1.98 (m, 1H), 1.90-1.75 (m, 3H), 1.72-1.41 (m, 8H) hLPA1 IC₅₀= 553 nM (1S,3S)-3-((6-(5-((((4- fluorobutyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 192

LCMS, [M + H]⁺ = 478.4 ¹H NMR (400 MHz, CDCl₃) δ 11.11 (br s, 1H), 8.18(d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 5.58-5.39 (m, 2H), 4.90(br s, 1H), 4.57- 4.49 (m, 1H), 4.46-4.35 (m, 1H), 4.23 (d, J = 4.2 Hz,3H), 3.35 (br d, J = 7.0 Hz, 2H), 3.03- 2.69 (m, 7H), 2.24-1.57 (m, 12H)¹⁹F NMR: 219 ppm hLPA1 IC₅₀ = 36 nM (1S,3S)-3-((6-(5-((((4-fluorobutyl)(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 193

LCMS, [M + H]⁺ = 446.1 ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J = 8.6 Hz,1H), 7.20 (d, J = 8.6 Hz, 1H), 5.77 (br d, J = 5.3 Hz, 2H), 4.38- 4.21(m, 1H), 4.15 (s, 3H), 3.34-3.06 (m, 2H), 2.98-2.79 (m, 3H), 2.60- 2.38(m, 5H), 2.21- 1.94 (m, 3H), 1.81-1.66 (m, 1H), 1.63-1.33 (m, 7H),0.97-0.70 (m, 2H) hLPA1 IC₅₀ = 1696 nM(1R,3R)-3-((2-methyl-6-(1-methyl-5- (((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylicacid

The following analogs were synthesized according to the methodsdescribed for the preparation of Example 1 except that the intermediate3 was used (instead of Example 1F).

Intermediate 3 was prepared from 2,5-dibromo-6-ethyl-pyridine using thesame synthetic sequence as described for the preparation of Example 1.

Example Structure & Name Analytical & Biology Data Method 194

LCMS, [M + H]⁺ = 472.0 ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (br d, J = 7.9Hz, 1H), 7.50 (br d, J = 8.5 Hz, 1H), 5.69 (br d, J = 16.2 Hz, 2H), 4.81(br s, 1H), 4.14 (s, 3H), 3.56 (br s, 1H), 3.10 (br s, 1H), 2.99 (br s,1H), 2.89-2.78 (m, 5H), 2.10- 2.02 (m, 1H), 1.90 (br d, J = 11.6 Hz,1H), 1.86-1.78 (m, 2H), 1.69-1.48 (m, 4H), 1.31-1.20 (m, 3H), 1.03-0.86(m, 1H), 0.85-0.66 (m, 1H), 0.45 (br s, 1H), 0.28 (br s, 1H), 0.22 (brs, 1H), 0.00 (br s, 1H) hLPA1 IC₅₀ = 14 nM Example 1 195

LCMS, [M + H]+ = 485.9 ¹H NMR (500 MHz, DMSO-d₆) δ 7.94-7.76 (m, 1H),7.60- 7.41 (m, 1H), 5.66 (s, 2H), 4.88- 4.62 (m, 1H), 2.80 (q, J = 7.3Hz, 2H), 2.64 (br s, 3H), 2.01- 1.92 (m, 1H), 1.92-1.86 (m, 1H),1.85-1.72 (m, 4H), 1.67- 1.58 (m, 5H), 1.54 (br s, 5H), 1.43 (br s, 5H),1.24 (br t, J = 7.4 Hz, 3H) hLPA1 IC₅₀ = 11 nM 196

LCMS, [M + H]+ = 486.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.2Hz, 1H), 7.50 (br d, J = 8.6 Hz, 1H), 5.66 (br d, J = 16.0 Hz, 2H), 4.75(br s, 1H), 4.10 (br d, J = 9.4 Hz, 3H), 2.80 (br d, J = 6.4 Hz, 2H),2.73 (br d, J = 17.7 Hz, 3H), 1.91 (br d, J = 14.9 Hz, 2H), 1.84 (s,6H), 1.76 (s, 4H), 1.71-1.57 (m, 4H), 1.54 (br s, 2H), 1.43 (br d, J =8.1 Hz, 1H), 1.25 (br d, J = 6.8 Hz, 3H) hLPA1 IC₅₀ = 12 nM 197

LCMS, [M + H]⁺ = 474.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (br t, J = 8.1Hz, 1H), 7.45 (br d, J = 8.2 Hz, 1H), 5.63 (br d, J = 18.3 Hz, 2H), 4.75(br s, 1H), 4.08 (br s, 3H), 2.99 (br d, J = 7.0 Hz, 1H), 2.85 (br d, J= 6.7 Hz, 1H), 2.81-2.70 (m, 5H), 1.97 (br d, J = 13.7 Hz, 1H), 1.86 (s,1H), 1.79 (br d, J = 12.5 Hz, 3H), 1.60 (br d, J = 8.9 Hz, 3H),1.57-1.45 (m, 2H), 1.23 (br d, J = 7.6 Hz, 3H), 0.78 (br d, J = 5.5 Hz,3H), 0.59-0.54 (m, 3H) hLPA1 IC₅₀ = 27 nM 198

LCMS, [M + H]⁺ = 494.0 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.3Hz, 2H), 7.47 (br d, J = 8.5 Hz, 1H), 7.32- 7.27 (m, 2H), 7.22 (br d, J= 7.2 Hz, 3H), 5.69 (s, 2H), 4.76 (br s, 1H), 4.18 (br d, J = 5.9 Hz,2H), 4.08 (s, 3H), 3.50 (br s, 1H), 2.78 (q, J = 7.3 Hz, 2H), 1.98 (brd, J = 13.0 Hz, 1H), 1.80 (br d, J = 11.8 Hz, 3H), 1.61 (br s, 2H), 1.54(br s, 1H), 1.50 (br s, 1H), 1.22 (br t, J = 7.4 Hz, 3H) hLPA1 IC₅₀ = 46nM 199

LCMS, [M + H]⁺ = 474.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.3Hz, 1H), 7.46 (br d, J = 8.3 Hz, 1H), 5.64 (br d, J = 12.4 Hz, 2H), 4.76(br s, 1H), 4.09 (br s, 3H), 3.53 (br s, 1H), 3.17 (br s, 1H), 3.03 (brs, 1H), 2.82-2.69 (m, 5H), 1.98 (br d, J = 13.8 Hz, 1H), 1.79 (br d, J =11.0 Hz, 3H), 1.60 (br s, 2H), 1.57-1.45 (m, 2H), 1.41 (br s, 1H),1.26-1.16 (m, 5H), 1.01-0.93 (m, 1H), 0.86 (br s, 1H), 0.61 (br s, 2H)hLPA1 IC₅₀ = 7 nM 200

LCMS, [M + H]⁺ = 460.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.92-7.70 (m, 1H),7.62- 7.30 (m, 1H), 5.80-5.48 (m, 2H), 4.89-4.58 (m, 1H), 4.24- 3.82 (m,3H), 3.60-3.25 (m, 1H), 3.21-2.93 (m, 2H), 2.85- 2.67 (m, 5H), 2.66-2.56(m, 1H), 2.07-1.94 (m, 1H), 1.90- 1.69 (m, 3H), 1.68-1.36 (m, 5H),1.33-1.14 (m, 3H), 0.86- 0.67 (m, 2H), 0.67-0.40 (m, 2H) hLPA1 IC₅₀ = 11nM 201

LCMS, [M + H]⁺ = 474.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.3Hz, 1H), 7.46 (br d, J = 8.3 Hz, 1H), 5.64 (br d, J = 12.4 Hz, 2H), 4.76(br s, 1H), 4.09 (br s, 3H), 3.53 (br s, 1H), 3.17 (br s, 1H), 3.03 (brs, 1H), 2.82-2.69 (m, 5H), 1.98 (br d, J = 13.8 Hz, 1H), 1.79 (br d, J =11.0 Hz, 3H), 1.60 (br s, 2H), 1.57-1.45 (m, 2H), 1.41 (br s, 1H),1.26-1.16 (m, 5H), 1.01-0.93 (m, 1H), 0.86 (br s, 1H), 0.61 (br s, 2H)hLPA1 IC₅₀ = 25 nM 202

LCMS, [M + H]⁺ = 446.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.5Hz, 1H), 7.47 (br d, J = 8.5 Hz, 1H), 5.66 (br s, 2H), 4.76 (br s, 1H),4.09 (s, 3H), 3.56-3.37 (m, 1H), 3.19 (br d, J = 18.6 Hz, 1H), 3.11 (brs, 1H), 2.82-2.75 (m, 3H), 2.73 (br s, 2H), 2.60-2.53 (m, 1H), 1.98 (brd, J = 13.4 Hz, 1H), 1.80 (br d, J = 11.0 Hz, 2H), 1.61 (br s, 2H), 1.53(br d, J = 16.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H), 1.00 (br d, J = 6.1Hz, 2H), 0.86 (br s, 2H) hLPA1 IC₅₀ = 160 nM 203

LCMS, [M + H]⁺ = 472.1 1H NMR (500 MHz, DMSO-d₆) δ 7.81 (br d, J = 8.2Hz, 1H), 7.46 (br d, J = 8.9 Hz, 1H), 5.62 (s, 2H), 4.74 (br s, 1H),4.07 (s, 3H), 3.77-3.70 (m, 4H), 2.77 (q, J = 7.3 Hz, 2H), 2.70 (br s,2H), 2.03 (br s, 1H), 1.93 (br d, J = 13.1 Hz, 2H), 1.88-1.72 (m, 5H),1.63-1.41 (m, 6H), 1.21 (br t, J = 7.3 Hz, 3H) hLPA1 IC₅₀ = 8 nM 204

LCMS, [M + H]⁺ = 472.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (br d, J = 8.5Hz, 1H), 7.46 (br d, J = 8.5 Hz, 1H), 5.62 (s, 2H), 4.74 (br s, 1H),4.05 (s, 3H), 3.79-3.70 (m, 4H), 2.78 (q, J = 7.3 Hz, 2H), 1.91 (br s,1H), 1.86-1.73 (m, 5H), 1.64- 1.44 (m, 4H), 1.22 (t, J = 7.5 Hz, 3H),1.13 (s, 6H) hLPA1 IC₅₀ = 102 nM 205

LCMS, [M + H]⁺ = 470.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J = 7.3Hz, 1H), 7.48 (br s, 1H), 5.62 (br s, 2H), 4.99-4.53 (m, 1H), 4.07 (brs, 2H), 3.58 (br s, 1H), 3.17 (s, 1H), 2.89 (s, 1H), 2.82 (br s, 1H),2.73 (s, 1H), 2.35 (br s, 1H), 2.05 (br s, 1H), 1.90 (br s, 7H), 1.64(br s, 4H), 1.25 (br s, 3H), 1.00 (d, J = 6.1 Hz, 1H) hLPA1 IC₅₀ = 842nM 206

LCMS, [M + H]⁺ = 484.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.88-7.75 (m, J = 8.2Hz, 1H), 7.54-7.41 (m, J = 8.2 Hz, 1H), 5.63 (s, 2H), 4.88-4.67 (m, 1H),4.09 (s, 2H), 3.69-3.53 (m, 1H), 3.17 (s, 1H), 2.89 (s, 1H), 2.80 (br d,J = 7.3 Hz, 2H), 2.76-2.63 (m, 3H), 2.05 (br s, 1H), 1.79 (br s, 8H),1.61 (br s, 4H), 1.22 (br t, J = 7.3 Hz, 3H), 1.00 (d, J = 6.4 Hz, 1H)hLPA1 IC₅₀ = 34 nM 207

LCMS, [M + H]⁺ = 500.4 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5Hz, 1H), 7.47 (br d, J = 8.5 Hz, 1H), 5.64 (br d, J = 8.5 Hz, 2H), 4.78(br s, 1H), 4.12 (s, 2H), 4.08 (br s, 1H), 2.83-2.73 (m, 4H), 2.73- 2.65(m, 1H), 2.60 (br s, 1H), 2.12-1.94 (m, 1H), 1.86 (br d, J = 12.2 Hz,1H), 1.82-1.70 (m, 2H), 1.66-1.52 (m, 3H), 1.52- 1.37 (m, 2H), 1.31-1.22(m, 4H), 1.20 (br s, 1H), 1.06 (br d, J = 8.2 Hz, 1H), 1.00 (d, J = 6.1Hz, 1H), 0.84 (br s, 1H), 0.74 (br s, 1H), 0.68-0.54 (m, 4H), 0.44 (brs, 1H) hLPA1 IC₅₀ = 133 nM 208

LCMS, [M + H]⁺ = 488.3 ¹H NMR (500 MHz, DMSO-d₆) δ 7.89-7.77 (m, J = 8.5Hz, 1H), 7.53-7.41 (m, J = 8.5 Hz, 1H), 5.64 (br s, 2H), 4.76 (br s,1H), 4.09 (s, 3H), 3.27-3.10 (m, 1H), 3.04 (br s, 1H), 2.89 (s, 1H),2.82-2.67 (m, 5H), 1.98 (br d, J = 12.8 Hz, 1H), 1.89 (s, 3H), 1.80 (brd, J = 11.6 Hz, 2H), 1.61 (br d, J = 8.5 Hz, 2H), 1.54 (br s, 1H), 1.49(br d, J = 11.3 Hz, 1H), 1.30 (br d, J = 5.8 Hz, 1H), 1.24 (br t, J =7.5 Hz, 3H), 1.12 (br s, 1H), 0.86 (br s, 3H), 0.60 (br s, 3H) hLPA1IC₅₀ = 26 nM 209

LCMS, [M + H]⁺ = 486.4 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 7.6Hz, 1H), 7.46 (br d, J = 8.5 Hz, 1H), 5.65 (br d, J = 10.7 Hz, 2H), 4.77(br s, 1H), 4.09 (br s, 3H), 3.24 (br s, 1H), 3.12 (br s, 1H), 2.95-2.85 (m, 1H), 2.83-2.71 (m, 5H), 2.61 (br t, J = 10.5 Hz, 1H), 2.08-1.95(m, 1H), 1.92-1.82 (m, 2H), 1.82-1.73 (m, 2H), 1.66-1.45 (m, 4H), 1.33(br s, 1H), 1.28-1.11 (m, 4H), 0.35 (br s, 1H), 0.16 (br s, 1H), −0.01(br s, 1H), −0.27 (br s, 1H) hLPA1 IC₅₀ = 22 nM 210

LCMS, [M + H]⁺ = 484.4 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.46 (d, J = 8.5 Hz, 1H), 5.64 (s, 2H), 4.77 (br s, 1H), 4.07 (s,3H), 2.93-2.86 (m, 1H), 2.80 (q, J = 7.3 Hz, 2H), 2.73 (s, 1H), 2.61 (brt, J = 10.7 Hz, 1H), 2.09-1.99 (m, 5H), 1.93-1.82 (m, 3H), 1.82-1.67 (m,4H), 1.65- 1.52 (m, 3H), 1.50 (br s, 1H), 1.28-1.14 (m, 3H) hLPA1 IC₅₀ =67 nM 211

LCMS, [M + H]+ = 484.4 ¹H NMR (500 MHz, DMSO-d₆) δ 7.87-7.80 (m, 1H),7.46 (br d, J = 8.9 Hz, 1H), 5.69 (br d, J = 5.8 Hz, 2H), 4.77 (br s,1H), 4.09 (br d, J = 15.3 Hz, 3H), 3.15 (s, 1H), 3.07 (s, 1H), 2.89 (s,1H), 2.80 (q, J = 7.6 Hz, 2H), 2.73 (s, 1H), 2.61 (br t, J = 10.5 Hz,1H), 2.16-1.96 (m, 1H), 1.91-1.74 (m, 3H), 1.70 (t, J = 6.9 Hz, 2H),1.65-1.45 (m, 4H), 1.29-1.14 (m, 3H), 0.55 (br s, 1H), 0.53-0.45 (m, 3H)hLPA1 IC₅₀ = 47 nM

The following analogs were synthesized according to the methodsdescribed for the preparation of Example 1 except that the intermediate4 was used (instead of Example 1F).

Intermediate 3 was prepared from 2,5-dibromo-pyrazine using the samesynthetic sequence as described for the preparation of Example 1.

Example Structure & Name Analytical & Biology Data Method 212

LCMS, [M + H]+ = 447.1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.34(s, 1H), 5.53 (br d, J = 15.0 Hz, 2H), 5.36 (br s, 1H), 4.12 (s, 3H),3.16 (br s, 1H), 3.06 (br s, 1H), 2.74 (br d, J = 11.6 Hz, 3H), 2.66 (brt, J = 10.1 Hz, 1H), 2.07 (br d, J = 13.1 Hz, 1H), 1.87-1.79 (m, 3H),1.66 (br t, J = 13.0 Hz, 2H), 1.60-1.48 (m, 2H), 1.41 (br s, 1H), 1.22(br s, 2H), 1.06-0.99 (m, 1H), 0.86 (br s, 1H), 0.68 (br s, 2H) hLPA1IC₅₀ = 40 nM Example 1 213

LCMS, [M + H]+ = 445.1 ¹H NMR (500 MHz, DMSO-d₆) δ 8.80-8.73 (m, 1H),8.37- 8.30 (m, 1H), 5.54 (br d, J = 13.1 Hz, 2H), 5.40-5.31 (m, 1H),4.12 (s, 3H), 3.12-3.02 (m, 1H), 3.02-2.92 (m, 1H), 2.83 (br s, 3H),2.70-2.60 (m, 1H), 2.12-2.01 (m, 1H), 1.86-1.79 (m, 3H), 1.71-1.61 (m,2H), 1.59-1.48 (m, 2H), 0.98-0.85 (m, 1H), 0.85-0.70 (m, 1H), 0.49-0.36(m, 1H), 0.36-0.23 (m, 1H), 0.23-0.09 (m, 1H), 0.09-−0.07 (m, 1H) hLPA1IC₅₀ = 1070 nM Example 1 214

LCMS, [M + H]+ = 459.0 ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.33(br s, 1H), 5.51 (br d, J = 16.5 Hz, 2H), 5.34 (br s, 1H), 4.12 (br s,3H), 3.56 (br s, 1H), 3.18 (br d, J = 10.4 Hz, 1H), 3.08 (br d, J = 5.5Hz, 1H), 2.71 (br d, J = 9.5 Hz, 3H), 2.64 (br s, 1H), 2.34-2.19 (m,1H), 2.08-2.02 (m, 1H), 1.90 (br s, 1H), 1.86-1.78 (m, 3H), 1.75 (br s,1H), 1.71 (br s, 1H), 1.64 (br d, J = 13.4 Hz, 3H), 1.59- 1.46 (m, 3H),1.40 (br s, 1H) hLPA1 IC₅₀ = 68 nM Example 1 215

LCMS, [M + H]+ = 459.3 ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.34(s, 1H), 5.54 (s, 2H), 5.35 (br s, 1H), 4.47-4.22 (m, 1H), 4.11 (s, 3H),3.53-3.31 (m, 1H), 2.63 (br s, 4H), 2.10-2.03 (m, 1H), 1.87-1.76 (m,3H), 1.73-1.60 (m, 3H), 1.57 (br s, 3H), 1.51 (br d, J = 12.2 Hz, 2H),1.43 (br s, 4H) hLPA1 IC₅₀ = 84 nM Example 1

Example 216 (1 S,3S)-3-((3-methyl-5-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylicacid

216A. Methyl 3-bromo-6-(3-hydroxyprop-1-yn-1-yl)pyrazine-2-carboxylate

A mixture of methyl 3,6-dibromopyrazine-2-carboxylate (16.5 g, 55.8mmol), propargyl alcohol (3.33 mL, 55.8 mmol), and TEA (46.6 mL, 335mmol) in MeCN (100 mL) was degassed with N₂ and then CuI (0.531 g, 2.79mmol) and bis(triphenylphosphine)Palladium(II) chloride (1.96 g, 2.79mmol) were successively added. The reaction mixture was degassed with N₂for 3 cycles & stirred at rt for 18 h, then was filtered through a padof Celite. The filtrate was concentrated in vacuo. The crude oil waschromatographed (120 g SiO₂ eluted with EtOAc/hexane using a continuousgradient from 0% to 80% over 25 min) to give the title product (5.40 g,19.9 mmol, 35.7% yield) as a brownish oil.

¹H NMR (500 MHz, CDCl₃) δ 8.53 (s, 1H), 4.56 (d, J=6.3 Hz, 2H), 4.04 (s,3H), 2.09-2.00 (m, 1H)

216B. Methyl3-bromo-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrazine-2-carboxylate

To a solution of Example 216A (2.7 g, 9.96 mmol) in 1,4-dioxane (100 mL)were successively added added TMSCH₂N₃ (1.48 mL, 9.96 mmol),chloro(pentamethylcyclopenta-dienyl)bis(triphenylphosphine)Ruthenium(II)(0.397 g, 0.498 mmol), and CuI (0.095 g, 0.498 mmol). The mixture wasdegassed with N₂ for 3 cycles. The resulting homogenous mixture was thenheated at 50° C. (oil bath) for 16 h, then was cooled to rt andconcentrated in vacuo. The residue was dissolved in THF (40 mL) andcooled to 0° C.; TBAF (19.9 mL of a 1 M solution in THF, 19.9 mmol) wasadded at 0° C. The reaction mixture was allowed to warm to rt andstirred at rt for 60 min, after which sat. aq. NaHCO₃ aqueous solution(20 mL) was added. The mixture was stirred for 1 h and filtered. Thefiltrate was concentrated in vacuo. The crude brown oily product waschromatographed (SiO₂; 80 g; elution with EtOAc/Hexane—continuousgradient from 0% to 80% over 25 min) to give title product (1.5 g, 4.57mmol, 45.9% yield) as a light brownish solid.

¹H NMR (400 MHz, CDCl₃) δ 9.42 (s, 1H), 4.90-4.85 (m, 3H), 4.15 (s, 3H),4.07 (s, 3H)

216C. Methyl3-bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazine-2-carboxylate

p-TsOH·H₂O (0.087 g, 0.457 mmol) was added to a solution of Example 216B(3.0 g, 9.14 mmol) and 3,4-dihydro-2H-pyran (2.502 mL, 27.4 mmol) in DCM(10 mL) at 0° C. The reaction mixture was stirred overnight at rt andneutralized with satd aq. NaHCO₃ to pH 7 at 0° C. The mixture waspartitioned between CH₂Cl₂ (10 mL) and water (10 mL), and the aqueouslayer was extracted with DCM (3×10 mL). The combined organic extractswere dried (MgSO₄), filtered, and concentrated in vacuo. The crude oilwas chromatographed (40 g SiO₂; elution with EtOAc/Hexane—continuousgradient from 0% to 50% over 25 min) to give the title compound (3.50 g,8.49 mmol, 93% yield) as light brownish oil.

[M-THP+H]⁺=328.1/330.1; ¹H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H),5.28-5.09 (m, 2H), 4.75-4.71 (m, 1H), 4.19 (s, 3H), 4.03 (s, 3H),3.82-3.75 (m, 1H), 3.53-3.45 (m, 1H), 1.85-1.44 (m, 6H)

216D.3-Bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazine-2-carboxylicacid

A solution of LiOH·H₂O (0.484 g, 11.53 mmol) in water (6 mL) was addeddropwise to a stirred solution of Example 216C (1.0 g, 2.43 mmol) in THF(6 mL) at 0° C. The reaction mixture was allowed to warm to rt andstirred at rt for 60 min, then was quenched carefully with 1N aq. HCl topH ˜5 at 0° C. and extracted with DCM (20×5 mL). The combined organicextracts were washed with brine and dried over Na₂SO₄. Volatiles wereremoved in vacuo to afford the title compound (0.80 g, 2.01 mmol, 83%yield) as a light yellowish solid.

[M-THP+H]⁺=313.9/315.9; ¹H NMR (500 MHz, CDCl₃) δ 9.46 (s, 1H), 5.42 (d,J=13.5 Hz, 1H), 4.90 (d, J=13.8 Hz, 1H), 4.24 (s, 3H), 3.87 (td, J=10.9,2.6 Hz, 1H), 3.73 (d, J=11.3 Hz, 1H), 1.93-1.50 (m, 7H)

217E.3-Bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazine-2-carbonylchloride

A mixture of Example 217D (228 mg, 0.573 mmol) and1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.114 mL, 0.859 mmol) in DCM(2 mL) was stirred at rt for 1 h. The reaction mixture was concentratedin vacuo to give the title compound (239 mg, 0.574 mmol, 100% yield) asyellowish oil which was used in the next reaction without furtherpurification.

218F.(3-Bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)methanol

A solution of Example 218E (3.14 g, 7.54 mmol) in THF (20 mL) was addeddropwise to a suspension of NaBH₄ (0.656 g, 17.33 mmol) in EtOH (20 mL)at −78° C. The reaction was stirred at −78° C. for 1 h. Aq. HCl (9.80 mLof a 1.0 N solution, 9.80 mmol) was added cautiously to the reaction tomake it weakly acidic at −78° C. The mixture was then basified withsat'd aq. NaHCO₃ to pH ˜8 and extracted with EtOAc (4×20 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuo.The crude oily product was chromatographed (40 g SiO₂; elution withEtOAc/Hexane (continuous gradient from 0% to 80% over 25 min) to givethe title compound (2.50 g, 6.51 mmol, 86% yield) as a light yellowishsolid.

¹H NMR (500 MHz, CDCl₃) δ 9.13 (s, 1H), 5.47 (d, J=13.2 Hz, 1H), 4.98(d, J=13.2 Hz, 1H), 4.89-4.85 (m, 2H), 4.76 (t, J=2.9 Hz, 1H), 4.69 (t,J=5.6 Hz, 1H), 4.19 (s, 3H), 3.93-3.81 (m, 1H), 3.62 (dt, J=10.9, 3.9Hz, 1H), 1.86-1.47 (m, 6H)

218G.2-Bromo-3-(chloromethyl)-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazine

To a solution of Example 218F (190 mg, 0.494 mmol) in CHCl₃ (3 mL) wasadded methanesulfonyl chloride (0.057 mL, 0.74 mmol), iPr₂NEt (0.259 mL,1.48 mmol) and DMAP (6.0 mg, 0.049 mmol) at 0° C. After the addition wascomplete, the reaction mixture was stirred at rt for 30 min. after whichLiCl (105 mg, 2.472 mmol) and DMF (3 mL) were successively added. Themixture was stirred at rt for 1 h and then concentrated in vacuo. Theresidue was partitioned between water and EtOAc (10 mL each). Theorganic phase was washed with brine, dried (MgSO₄) and concentrated invacuo. The crude oily product was chromatographed (12 g SiO₂; elutionwith EtOAc/Hexane (continuous gradient from 0% to 50% over 10 min) togive the title compound (175 mg, 0.435 mmol, 88% yield) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 5.33-5.19 (m, 2H), 4.84 (s, 2H),4.75 (t, J=3.4 Hz, 1H), 4.19 (s, 3H), 3.88-3.75 (m, 1H), 3.59-3.47 (m,1H), 1.87-1.46 (m, 6H)

218H.2-Bromo-3-methyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazine

To a 0° C. solution of NaBH₄ (286 mg, 7.55 mmol) in EtOH (20 mL) wasadded dropwise a solution of Example 218G (760 mg, 1.89 mmol) in THF (20mL). After the addition was complete, the reaction was stirred at rt for6 h. LCMS indicated the reaction was still not complete, so additionalNaBH₄ (286 mg, 7.55 mmol) was added and the reaction mixture was stirredfor 3 days, then cautiously quenched with water at 0° C. The mixture wasextracted with EtOAc (3×5 mL). The combined organic extracts were washedwith brine, dried (Na₂SO₄), and concentrated in vacuo. The crude oilyproduct was chromatographed (24 g SiO₂; elution with EtOAc/Hexane(continuous gradient from 0% to 50% over 10 min) to give the titlecompound (600 mg, 1.63 mmol, 86% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ 9.04 (s, 1H), 5.29-5.20 (m, 2H), 4.75 (t,J=3.4 Hz, 1H), 4.20 (s, 3H), 3.86 (ddd, J=11.3, 8.3, 3.0 Hz, 1H),3.59-3.50 (m, 1H), 2.72 (s, 3H), 1.85-1.49 (m, 6H)

218I.3-Methyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-ol

A mixture of Example 218H (600 mg, 1.63 mmol), KOH (1.00 mL of a 7 M aq.solution, 7.0 mmol) in water (5 mL) and dioxane (5 mL) was degassedunder N₂ and then tBuXphos (83 mg, 0.196 mmol) and Pd₂(dba)₃ (44.8 mg,0.049 mmol) were added. The reaction mixture was degassed under N₂ againand then stirred at 80° C. overnight. The reaction was cooled to rt,then was acidified to pH 5 with 1N aq. HCl at 0° C. and partitionedbetween water and EtOAc. The organic phase was separated, dried (MgSO₄),and concentrated in vacuo. The crude oily product was chromatographed(12 g SiO₂; elution with EtOAc/Hexane (continuous gradient from 0% to100% over 7 min) to give the title compound (340 mg, 1.11 mmol, 68.3%yield) as a light yellowish solid. [M-THP+H]⁺=222.2; ¹H NMR (500 MHz,CDCl₃) δ 8.04 (s, 1H), 5.24-5.15 (m, 2H), 4.88-4.72 (m, 1H), 4.16 (s,3H), 3.90 (ddd, J=11.2, 8.2, 3.2 Hz, 1H), 3.72-3.52 (m, 1H), 2.55 (s,3H), 1.90-1.44 (m, 7H)

218J. Isopropyl(1S,3S)-3-((3-methyl-5-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate

To a mixture of Example 2181 (340 mg, 1.11 mmol)), ((1S,3R)-isopropyl3-hydroxycyclo-hexane carboxylate (373 mg, 2.00 mmol) in THF (5 mL) weresuccessively added n-Bu₃P (0.556 mL, 2.227 mmol) and(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (562 mg, 2.23 mmol).The reaction mixture was then stirred at 80° C. for 18 h, then wascooled to rt and concentrated in vacuo. The crude oily product waschromatographed (24 g SiO₂; elution with EtOAc/Hexane (continuousgradient from 0% to 50% over 10 min) to give the title compound (527 mg,1.11 mmol, 100% yield) as a clear oil.

[M+H]⁺=474.2

218K. Isopropyl(1S,3S)-3-((5-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylate

A mixture of Example 218J (527 mg, 1.11 mmol) and pyridiniump-toluenesulfonate (28 mg, 0.11 mmol) in MeOH (10 mL) was stirred at rtfor 3 days and then concentrated in vacuo. The crude oily product waschromatographed (24 g SiO₂; elution with EtOAc/Hexane (continuousgradient from 0% to 100% over 10 min) to give the title compound (277mg, 0.711 mmol, 63.9% yield) as a clear oil. [M+H]⁺=390.2; ¹H NMR (500MHz, CDCl₃) δ 8.89 (s, 1H), 5.54 (br s, 1H), 5.04 (dt, J=12.4, 6.3 Hz,1H), 4.83 (s, 2H), 4.16-4.10 (m, 3H), 2.74 (tt, J=11.1, 3.9 Hz, 1H),2.56 (s, 3H), 2.23 (br d, J=14.0 Hz, 1H), 2.01 (br dd, J=8.8, 4.1 Hz,2H), 1.89 (ddd, J=13.9, 11.4, 2.8 Hz, 1H), 1.82-1.47 (m, 5H), 1.26 (dd,J=6.3, 2.8 Hz, 6H)

218L. Isopropyl(1S,3S)-3-((3-methyl-5-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylate

A solution of 4-nitrophenyl chloroformate (172 mg, 0.854 mmol) in DCM (1mL) was added dropwise to a solution of Example 218K (277 mg, 0.711mmol) and pyridine (0.288 mL, 3.56 mmol) in DCM (5 mL) over 1 h at 0° C.The reaction was then stirred at rt for 18 h, then was concentrated invacuo. The crude oily product was chromatographed (12 g SiO₂; elutionwith EtOAc/Hexane (continuous gradient from 0% to 50% over 10 min) togive the title compound (366 mg, 0.66 mmol, 93% yield) as a lightyellowish oil. [M+H]⁺=555.2; ¹H NMR (500 MHz, CDCl₃) δ 8.79 (s, 1H),8.33-8.28 (m, 2H), 7.44-7.37 (m, 2H), 6.02-5.94 (m, 2H), 5.52 (br s,1H), 5.03 (dt, J=12.6, 6.2 Hz, 1H), 4.23 (s, 3H), 2.74 (tt, J=11.1, 3.9Hz, 1H), 2.52 (s, 3H), 2.22 (br d, J=14.0 Hz, 1H), 2.03-1.96 (m, 2H),1.93-1.83 (m, 1H), 1.81-1.52 (m, 4H), 1.30-1.22 (m, 6H)

Example 218

To a solution of Example 218L (8 mg, 0.014 mmol) in DCM (1 mL) was addedN-methyl propan-1-amine (1.8 μL; 0.017 mmol) and DIPEA (7.6 μL, 0.043mmol). The reaction mixture was stirred at rt for 2 h, then wasconcentrated in vacuo. The crude oil was (4 g SiO₂; elution withEtOAc/Hexane (continuous gradient from 0% to 30% over 10 min) to givethe corresponding carbamate-isopropyl ester Example as a clear oil. Thisester intermediate was stirred with 1N aq. NaOH (0.2 mL) in THF (1 mL)and MeOH (0.2 mL) at rt for 18 h and then acidified to pH=−2 with TFA.The reaction mixture was purified by preparative HPLC (Sunfire C1830×100 mm-regenerated column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 20% B to 100% B over 10 min+2 min hold time at100% B, where A=90:10:0.1 H₂O:MeCN:TFA and B=90:10:0.1 MeCN:H₂O:TFA) togive Example 218 (5 mg, 11.0 μmol, 76% yield) as a clear oil.

[M+H]⁺=447.3; ¹H NMR (500 MHz, CDCl₃) δ 8.72 (s, 1H), 5.69 (br d, J=7.4Hz, 2H), 5.53 (br s, 1H), 4.18 (s, 3H), 3.26 (br t, J=7.2 Hz, 1H), 3.13(br t, J=7.2 Hz, 1H), 2.97-2.79 (m, 4H), 2.52 (s, 3H), 2.32 (br d,J=14.0 Hz, 1H), 2.16-1.99 (m, 2H), 1.93-1.37 (m, 7H), 0.98-0.71 (m, 3H).hLPA IC₅₀=194 nM

Example Structure & Name Analytical & Biology Data Method 219

LCMS, [M + H]⁺ = 461.4; ¹H NMR (500 MHz, CDCl₃) δ 8.69 (s, 1H), 5.68(br. s., 2H), 5.53 (br. s., 1H), 4.19 (s, 3H), 3.36-3.10 (m, 2H),2.97-2.79 (m, 4H), 2.53 (s, 3H), 2.32 (d, J = 14.0 Hz, 1H), 2.14-1.97(m, 2H), 1.94-1.12 (m, 9H), 1.02- 0.74 (m, 3H) hLPA1 IC₅₀ = 21 nMExample 218 (1S,3S)-3-((5-(5-(((butyl (methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-3- methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 220

LCMS, [M + H]⁺ = 458.9. ¹H NMR (500 MHz, DMSO-d₆): δ 8.57 (s, 1H), 5.54(d, J = 19.1 Hz, 2H), 5.38 (s, 1H), 4.10 (s, 3H), 3.05 (br s, 1H), 2.93(br s, 1H), 2.85-2.76 (m, 2H), 2.54 (s, 3H), 2.44 (s, 3H), 2.41-2.12 (m,8H). 0.40 (br s, 1H), 0.24 (br s, 1H), 0.16 (br s, 1H), −0.04 (br s,1H). hLPA IC₅₀ = 149 nM Example 218 (1S,3S)-3-((5-(5-((((cyclopropyl-methyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methyl- pyrazin-2- yl)oxy)cyclohexane-1-carboxylic acid221

LCMS, [M + H]⁺ = 473.2. ¹H NMR (500 MHz, CDCl₃): δ 8.66 (s, 1H), 5.64(br s, 2H), 5.51 (s, 1H), 4.17 (s, 3H), 3.31 (d, J = 7.5 Hz, 1H), 3.17(d, J = 7.3 Hz, 1H), 2.91-2.77 (m, 4H), 2.61-2.35 (m, 1H), 2.50 (s, 3H),2.29 (d, J = 14.1 Hz, 1H), 2.10-1.50 (m, 13H). hLPA1 IC₅₀ = 23 nMExample 218 (1S,3S)-3-((5-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 222

LCMS; [M + H]⁺ = 475.4; ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (br s, 1H),5.54 (br d, J = 13.0 Hz, 2H), 5.38 (br s, 1H), 4.12 (br s, 3H), 3.18 (brd, J = 9.2 Hz, 1H), 3.03 (br s, 1H), 2.80- 2.58 (m, 4H), 2.44 (br s,3H), 2.09 (br d, J = 13.6 Hz, 1H), 1.94-1.03 (m, 10H), 0.92-0.55 (m, 6H)hLPA1 IC₅₀ = 19 nM Example 218 (1S,3S)-3-((5-(5-(((isopentyl(methyl)carbamoyl)oxy)methyl)-1- methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy) cyclohexane-1-carboxylic acid 223

LCMS; [M + H]⁺ = 475.4; ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (s, 1H), 5.54(br d, J = 15.9 Hz, 2H), 5.37 (br s, 1H), 4.11 (br s, 2H), 3.22-2.99 (m,2H), 2.80-2.67 (m, 3H), 2.62- 2.53 (m, 4H), 2.44 (s, 2H), 2.13-1.96 (m,1H), 1.90- 0.59 (m, 15H) hLPA1 IC₅₀ = 56 nM Example 218(1S,3S)-3-((3-methyl-5-(1-methyl- 5-(((methyl(pentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4- yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 224

LCMS; [M + H]⁺ = 461.2; ¹H NMR (500 MHz, CDCl₃): δ 8.72 (s, 1H), 5.69(br d, J = 14.3 Hz, 2H), 5.53 (br s, 1H), 4.18 (s, 3H), 3.12 (br d, J =7.4 Hz, 1H), 3.03- 2.77 (m, 6H), 2.53 (s, 3H), 2.32 (br d, J = 14.0 Hz,1H), 2.18-1.53 (m, 7H), 0.99- 0.74 (m, 6H) hLPA1 IC₅₀ = 121 nM Example218 (1S,3S)-3-((5-(5- (((isobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 225

LCMS; [M + H]⁺ = 473.4; ¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (s, 1H), 5.54(br d, J = 14.4 Hz, 2H), 5.38 (br s, 1H), 4.11 (br s, 3H), 3.29-3.07 (m,2H), 2.82-2.70 (m, 3H), 2.57 (br d, J = 11.3 Hz, 1H), 2.43 (s, 3H),2.16-1.97 (m, 1H), 1.93-1.01 (m, 9H), 0.70- 0.12 (m, 3H), 0.06-−0.40 (m,2H) hLPA1 IC₅₀ = 70 nM Example 218 (1S,3S)-3-((5-(5-((((2-cyclopropylethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl) oxy)cyclohexane-1-carboxylic acid226

LCMS; [M + H]⁺ = 473.5; ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (s, 1H), 5.53(s, 2H), 5.38 (br s, 1H), 4.10 (s, 3H), 3.64 (br s, 1H), 2.62 (br s,4H), 2.44 (s, 3H), 2.19-2.02 (m, 1H), 1.95- 1.24 (m, 15H) hLPA1 IC₅₀ =49 nM Example 218 (1S,3S)-3-((5-(5- (((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 227

LCMS; [M + H]⁺ = 487.5; ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (s, 1H),5.61-5.48 (m, 2H), 5.40 (br s, 1H), 4.12 (br s, 3H), 3.20- 2.91 (m, 2H),2.84-2.69 (m, 3H), 2.64 (br s, 1H), 2.48-2.42 (m, 3H), 2.10 (br d, J =13.1 Hz, 1H), 1.96- 1.07 (m, 15H), 0.89 (br s, 1H) hLPA1 IC₅₀ = 18 nMExample 218 (1S,3S)-3-((5-(5- ((((cyclopentylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 228

LCMS; [M + H]⁺ = 495.3; ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (br s, 1H),7.38-7.04 (m, 4H), 6.96 (br s, 1H), 5.68-5.47 (m, 2H), 5.37 (br s, 1H),4.47-4.21 (m, 2H), 4.19-3.97 (m, 3H), 2.83-2.66 (m, 3H), 2.62 (br t, J =11.0 Hz, 1H), 2.46-2.32 (m, 3H), 2.13- 2.04 (m, 1H), 1.95-1.40 (m, 7H)hLPA1 IC₅₀ = 60 nM (1S,3S)-3-((5-(5- (((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 229

LCMS; [M + H]⁺ = 459.0; ¹H NMR (500 MHz, DMSO-d₆) δ 8.58-8.57 (m, 1H),5.54 (br s, 2H), 5.39 (br s, 1H), 4.10 (s, 4H), 2.82- 2.57 (m, 4H),2.47-2.39 (m, 3H), 2.18-1.31 (m, 14H) hLPA1 IC₅₀ = 76 nM(1S,3S)-3-((5-(5- (((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 230

LCMS; [M + H]⁺ = 465.4; ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (s, 1H), 5.56(br s, 2H), 5.39 (br s, 1H), 4.54-4.17 (m, 2H), 4.11 (s, 3H), 3.39-3.14(m, 2H), 2.89-2.69 (m, 3H), 2.64 (br t, J = 10.8 Hz, 1H), 2.45 (s, 3H),2.10 (br d, J = 13.7 Hz, 1H), 1.94-1.41 (m, 9H) hLPA1 IC₅₀ = 390 nM(1S,3S)-3-((5-(5-((((3- fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 231

LCMS; [M + H]⁺ = 475.2; ¹H NMR (500 MHz, CHLOROFORM-d) δ 8.71 (s, 1H),5.68 (br d, J = 12.1 Hz, 2H), 5.54 (br s, 1H), 4.23-4.16 (m, 3H), 3.14(s, 1H), 3.04-2.96 (m, 3H), 2.93-2.81 (m, 2H), 2.53 (s, 3H), 2.32 (br d,J = 14.0 Hz, 1H), 2.16-1.97 (m, 2H), 1.94-1.84 (m, 1H), 1.83- 1.55 (m,4H), 1.04-0.72 (m, 9H) hLPA1 IC₅₀ = 88 nM(1S,3S)-3-((3-methyl-5-(1-methyl- 5-(((methyl(neopentyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4- yl)pyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 232

LCMS; [M + H]⁺ = 479.2; ¹H NMR (500 MHz, CDCl₃): δ 8.67 (s, 1H), 5.80-5.57 (m, 2H), 5.54 (br s, 1H), 4.26-4.16 (m, 3H), 3.57-3.27 (m, 2H),3.10- 2.77 (m, 4H), 2.59-2.46 (m, 3H), 2.32 (br d, J = 13.8 Hz, 1H),2.13-1.97 (m, 2H), 1.95-1.53 (m, 5H), 1.42-1.13 (m, 6H); ¹⁹F NMR (471MHz, CDCl3): δ −139.12 (s, 1F) hLPA1 IC₅₀ = 191 nM(1S,3S)-3-((5-(5-((((2-fluoro-2- methylpropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 233

LCMS; [M + H]⁺ = 491.2; ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H), 5.69(br d, J = 5.1 Hz, 2H), 5.51 (br s, 1H), 4.16 (s, 3H), 3.72- 3.34 (m,2H), 3.04-2.75 (m, 4H), 2.49 (br d, J = 4.6 Hz, 3H), 2.33-1.49 (m, 14H);¹⁹F NMR (377 MHz, CDCl₃): δ −130.34 (br s, 1F) hLPA1 IC₅₀ = 122 nM(1S,3S)-3-((5-(5-(((((1-fluoro- cyclobutyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid 234

LCMS; [M + H]⁺ = 505.2; ¹H NMR (400 MHz, CDCl₃): δ 8.64 (s, 1H), 5.71-5.61 (m, 2H), 5.52 (br s, 1H), 4.19 (s, 3H), 3.68- 3.37 (m, 2H),3.07-2.91 (m, 3H), 2.84 (tt, J = 11.2, 3.7 Hz, 1H), 2.51 (d, J = 3.5 Hz,3H), 2.29 (br d, J = 13.9 Hz, 1H), 2.12-1.96 (m, 2H), 1.94-1.35 (m,13H); ¹⁹F NMR (377 MHz, CDCl₃): δ −139.45 to −147.94 (m, 1F) hLPA1 IC₅₀= 72 nM (1S,3S)-3-((5-(5-(((((1- fluorocyclopentyl)methyl)(methyl)carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)-3-methylpyrazin-2- yl)oxy)cyclohexane-1-carboxylic acid 235

LCMS; [M + H]⁺ = 473.0; ¹H NMR (500 MHz, CDCl₃): δ 8.72 (s, 1H), 5.82-5.56 (m, 2H), 5.53 (br s, 1H), 4.17 (s, 3H), 3.29- 2.80 (m, 6H), 2.52(s, 3H), 2.31 (br d, J = 14.0 Hz, 1H), 2.14-1.97 (m, 2H), 1.91- 1.54 (m,5H), 1.10-0.90 (m, 3H), 0.75-0.11 (m, 4H) hLPA1 IC₅₀ = 70 nM(1S,3S)-3-((3-methyl-5-(1-methyl- 5-(((methyl(((1R,2R)-2-methylcyclopropyl)methyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1- carboxylic acid 236

LCMS; [M + H]⁺ = 473.0; ¹H NMR (500 MHz, CDCl₃): δ 8.72 (s, 5H), 5.69(br d, J = 6.9 Hz, 2H), 5.52 (br s, 1H), 4.17 (s, 3H), 3.28- 2.80 (m,6H), 2.58-2.46 (m, 3H), 2.31 (br d, J = 13.8 Hz, 1H), 2.12-1.97 (m, 2H),1.93-1.54 (m, 5H), 1.10-0.89 (m, 3H), 0.74- 0.11 (m, 4H) hLPA1 IC₅₀ = 46nM (1S,3S)-3-((3-methyl-5-(1-methyl- 5-(((methyl(((1S,25)-2-methylcyclopropyl)methyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)oxy)cyclohexane-1- carboxylic acid

Example 237(1S,3S)-3-((5-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylicacid

237A. Isopropyl(1S,3S)-3-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylate

To a N₂-flushed, 50 mL round bottom flask was added(E)-diazene-1,2-diylbis (piperidin-1-ylmethanone) (2.11 g, 8.35 mmol),toluene (15 mL) and n-Bu₃P (2.1 mL, 8.35 mmol); the dark orange solutionbecame a light yellow solution after the addition of n-Bu₃P. Thesolution was stirred at rt for 30 min, then5-bromo-3-(trifluoromethyl)pyridin-2-ol (1.01 g, 4.17 mmol) and(1S,3R)-isopropyl 3-hydroxycyclohexanecarboxylate (1.40 g, 7.51 mmol)were successively added. The reaction mixture was heated to 80° C. for16 h, then was cooled to rt. EtOAc (10 mL) and water (5 mL) were added,and the mixture was stirred for 10 min and the organic layer wasseparated. The aqueous layer was back-extracted with EtOAc (2×10 mL).The combined organic extracts were washed with brine (10 mL), dried(MgSO₄), and concentrated in vacuo to give the crude product. This crudematerial was chromatographed (SiO₂, 120 g; elution with EtOAc/hexanes(continuous gradient from 0 to 100%) to afford the title compound (1.7g, 4.14 mmol, 99% yield) as a colorless oil.

¹H NMR (500 MHz, CDCl₃): δ 8.32 (d, J=2.4 Hz, 1H), 7.93 (d, J=2.5 Hz,1H), 5.52 (br s, 1H), 5.06-4.94 (m, 1H), 2.69 (tt, J=11.6, 3.9 Hz, 1H),2.23-2.17 (m, 1H), 2.03-1.93 (m, 2H), 1.82-1.43 (m, 5H), 1.22 (d, J=6.3Hz, 6H). LCMS, [M+H]⁺=410.

237B. Isopropyl(1S,3S)-3-((5-(3-hydroxyprop-1-yn-1-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylate

To a 100 mL round bottom flask containing Example 237A (1.7 g, 4.1 mmol)and prop-2-yn-1-ol (0.70 g, 12.4 mmol) in MeCN (21 ml) was added Et₃N(2.89 mL, 20.7 mmol). The solution was quickly degassed (evacuationunder vacuum, then refill with N₂ (3×)). Trans-dichlorobis(triphenylphosphine) palladium (II) chloride (0.29 g, 0.41 mmol) and CuI(0.039 g, 0.21 mmol) were added. The solution degassed (evacuation undervacuum, then refill with N₂ (3×)). The reaction was heated to reflux at80° C. for 24 h, then was cooled to rt. The reaction mixture wasfiltered through a Celite® plug, which was washed with EtOAc (2×10 mL).The combined filtrates were concentrated in vacuo and the residue waschromatographed (40 g SiO₂; continuous gradient from 0% to 100% EtOAc inHexanes for 20 min) to give the title compound as a white solid (1.13 g,2.93 mmol, 71% yield). ¹H NMR (400 MHz, CDCl3) δ 8.35 (d, J=2.4 Hz, 1H),7.88 (d, J=2.5 Hz, 1H), 5.58 (br s, 1H), 5.06-4.97 (m, 1H), 4.50 (d,J=6.2 Hz, 2H), 2.70 (tt, J=11.6, 3.9 Hz, 1H), 2.24-2.17 (m, 1H),2.03-1.93 (m, 2H), 1.82-1.43 (m, 5H), 1.22 (d, J=6.3 Hz, 6H). LCMS,[M+H]⁺=386.2.

237C. Isopropyl(1S,3S)-3-((5-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylate

To a solution of Example 237B (1.13 g, 2.9 mmol) in 1,4-dioxane (20 mL)was added TMSCH₂N₃ (0.68 g, 5.3 mmol),chloro(pentamethylcyclopentadienyl)bis(triphenyl-phosphine)Ruthenium(II)(0.12 g, 0.15 mmol), and CuI (0.028 g, 0.15 mmol). The mixture wasquickly evacuated and backfilled with N₂ (this sequence was repeatedthree times). The resulting homogenous mixture was then heated in a 50°C. oil bath for 16 h (when the external and internal temp. are between49 to 50° C.), then was cooled to rt and concentrated on a rotaryevaporator to dryness (the waste trap content was collected, labeled asazide-containing hazardous waste and disposed accordingly). The residuewas dissolved in THF (20 mL). TBAF (5.86 mL of a 1 M solution in THF,5.86 mmol) was added and the mixture was stirred at rt for 60 min. Thereaction was quenched with sat'd aq. NaHCO₃ (20 mL) and extracted withEtOAc (4×20 mL). The combined organic extracts were washed with brine(20 mL), dried (MgSO₄) and concentrated in vacuo. The crude waschromatographed (continuous gradient from 0% to 70% EtOAc/hexanes over27 min, then gradient from 70 to 100% in 8 min; 80 g Gold ISCO SiO₂column) and then preparative HPLC under the following conditions:Column: Phenomenex Luna 5 u C18 100A 30×250 mm; Mobile Phase A: 10:90MeCN:H₂O with 0.1% TFA; Mobile Phase B: 90:10 MeCN:H₂O with 0.1% TFA;Gradient: 0-100% B over 20 min, then a 5-min hold at 100% B; Flow: 30mL/min. Fractions containing the desired product were combined and driedvia centrifugal evaporation to afford the title compound (0.50 g, 1.13mmol, 38.5% yield) (the later eluting fraction). ¹H NMR (400 MHz, CDCl3)δ 8.55 (d, J=2.5 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H), 5.62 (br s, 1H),5.06-4.99 (m, 1H), 4.86 (s, 2H), 4.18 (s, 3H), 2.73 (tt, J=11.5, 3.8 Hz,1H), 2.28-2.22 (m, 1H), 2.05-1.98 (m, 2H), 1.85-1.45 (m, 5H), 1.22 (d,J=6.2 Hz, 6H). The regiochemistry of this desired product was determinedby 1D-NoE NMR experiments. LCMS, [M+H]⁺=443.2.

237D. Isopropyl(1S,3S)-3-((5-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylate

To a solution of Example 237C (116 mg, 0.26 mmol) and 4-nitrophenylchloroformate (106 mg, 0.52 mmol) in DCM (3 mL) was added pyridine(0.085 mL, 1.05 mmol) at rt. A white solid was formed. The reactionmixture was stirred at rt for 16 h, after which the solid was filteredoff and washed with DCM. The combined filtrate and washes wereevaporated in vacuo. The crude product was chromatographed (12 g SiO₂,elution with continuous gradient from 0 to 100% EtOAc in DCM) to givethe title compound (114 mg, 0.19 mmol, 71.6% yield) as a white solid. ¹HNMR (500 MHz, CDCl₃) δ 8.65 (d, J=2.2 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H),8.31 (d, J=9.1 Hz, 2H), 7.40 (d, J=9.1 Hz, 2H), 5.64 (br s, 1H), 5.45(s, 2H), 5.06-4.99 (m, 1H), 4.25 (s, 3H), 2.74 (t, J=11.7 Hz, 1H),2.29-2.22 (m, 1H), 2.05-1.98 (m, 2H), 1.86-1.45 (m, 5H), 1.22 (d, J=6.2Hz, 6H). LCMS, [M+H]⁺=608.3.

Example 237

To a solution of Example 237D (5.4 mg, 8.9 μmol) and1-cyclopropyl-N-methylmethanamine (2.0 μL, 0.018 mmol) in THF (0.4 mL)was added N-ethyl-N-isopropyl-propan-2-amine (5 μL, 0.027 mmol). Themixture was stirred at rt for 1 h, after which a solution of LiOH·H₂O(3.7 mg, 0.088 mmol) in water (0.4 mL) and MeOH (0.2 mL) was added. Thereaction mixture was stirred at rt for 48 h, then was acidified to pH E4 with 1N aq. HCl and extracted with EtOAc (3×5 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 19×200 5 mm, 5-μm particles; MobilePhase A: 5:95 MeCN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 MeCN:H₂Owith 10 mM NH₄OAc; Continuous gradient: 20-60% B over 20 min, then a4-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (2.4 mg, 51% yield).

The following compounds were prepared by the general synthetic schemefor Example 237.

Analytical & Biology Example Structure & Name Data Method 237

LCMS, [M + H]⁺ = 512.0. ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.32(s, 1H), 5.55 (br s, 1H), 5.33 (s, 2H), 4.12 (s, 3H), 2.71 (s, 3H),2.66-2.58 (m, 1H), 2.54 (s, 2H), 2.41-2.12 (m, 9H). 0.41 (br s, 1H),0.25 (br s, 1H), 0.18 (br s, 1H), −0.01 (br s, 1H). hLPA1 IC₅₀ = 2400 nMExample 237 (1S,3S)-3-((5-(5- ((((cyclopropylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-3-(trifluoromethyl)pyridin-2- yl)oxy)cyclohexane-1-carboxylic acid 238

LCMS, [M + H]⁺ = 526.0. ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.12(s, 1H), 5.32 (br s, 1H), 5.15 (s, 1H), 5.11 (s, 1H), 3.91 (s, 3H),3.0-2.85 m, 3H), 2.50 (s, 3H), 1.88-1.13 (m, 15H). hLPA1 IC₅₀ = 174 nM(1S,3S)-3-((5-(5- (((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid 239

LCMS, [M + H]⁺ = 512.5. ¹H NMR (500M Hz, DMSO-d₆) δ 8.76 (s, 1H), 8.34(s, 1H), 5.55 (br s, 1H), 5.33 (s, 2H), 4.12 (s, 3H), 2.71 (s, 3H), 2.54(s, 2H), 2.12-1.36 (m, 14H). hLPA1 IC₅₀ = 440 nM (1S,3S)-3-((5-(5-((((cyclobutylmethyl)(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-3- (trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid 240

LCMS, [M + H]⁺ = 526.0. ¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.36(s, 1H), 5.57 (br s, 1H), 5.37 (br s, 2H), 4.14 (s, 3H), 2.64 (s, 3H),2.59-2.52 (m, 2H), 2.15-1.32 (m, 16H). hLPA1 IC₅₀ = 1207 nM(1S,3S)-3-((5-(5- (((cyclobutyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4- yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid

Example 241(1S,3S)-3-((6-(5-(2-(((Cyclobutylmethyl)(methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

241A. Methyl(1S,3S)-3-((6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a stirred solution of methyl(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(3.28 g, 9.10 mmol) in CH₂Cl₂ (45.5 ml) were added NaHCO₃ (3.82 g, 45.5mmol) and Dess-Martin periodinane (4.63 g, 10.9 mmol) and the reactionmixture was stirred at rt for 1 h. The white solid was filtered offthrough Celite© and rinsed with EtOAc. The combined filtrates werewashed with sat. aq. NaHCO₃, water, brine, dried over Na₂SO₄, filteredand concentrated in vacuo. The crude product was chromatographed (120 gRedisep® SiO₂ column; isocratic 60% EtOAc in Hex) to afford the titlecompound as a clear, colorless oil (3.10 g, 95%). LC-MS, [M+H]⁺=359.1.¹H NMR (500 MHz, CDCl₃) δ 10.96 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.24(d, J=8.5 Hz, 1H), 4.77-4.72 (m, 1H), 4.36 (s, 3H), 3.70 (s, 3H),2.87-2.80 (m, 1H), 2.51 (s, 3H), 2.20-2.08 (m, 1H), 2.02-1.91 (m, 3H),1.80-1.59 (m, 4H).

241B Methyl(1S,3S)-3-((2-methyl-6-(1-methyl-5-vinyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a cooled (0° C.) suspension of methyltriphenylphosphonium bromide(3.77 g, 10.55 mmol) in THF (70.3 mL) was added KOtBu (0.947 g, 8.44mmol), and the reaction mixture was stirred at 0° C. for 30 min. To thisreaction mixture was added a solution of Example 241A (2.52 g, 7.03mmol) in THF (10 mL). The reaction was stirred at 0° C. for 30 min, thenwas allowed to warm to rt. After 1 h at rt, the reaction was quenchedwith sat. aq. NH₄Cl, then was diluted with EtOAc. The aqueous layer wasextracted with EtOAc (2×25 mL). The combined organic extracts werewashed with brine, dried (Na₂SO₄), and concentrated in vacuo. The crudeproduct was chromatographed (220 g Redisep® SiO₂ column; continuousgradient from 0-60% EtOAc in Hex) to afford the title compound as awhite gum (2.2 g, 88%). LC-MS, [M+H]⁺=357.0. ¹H NMR (500 MHz, CDCl₃) δ7.91 (d, J=8.5 Hz, 1H), 7.42 (dd, J=18.3, 12.0 Hz, 1H), 7.20 (d, J=8.5Hz, 1H), 5.93-5.88 (m, 1H), 5.70-5.66 (m, 1H), 4.71 (br s, 1H), 4.15 (s,3H), 3.70 (s, 3H), 2.84 (tt, J=10.5, 3.9 Hz, 1H), 2.53 (s, 3H), 2.16 (brd, J=13.8 Hz, 1H), 2.02-1.87 (m, 3H), 1.87-1.71 (m, 1H), 1.71-1.54 (m,3H).

241C Methyl(1S,3S)-3-((6-(5-(2-hydroxyethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a cooled (0° C.) solution of Example 241B (1.45 g, 4.07 mmol) in THF(13.6 ml) was added dropwise 9-BBN (17.9 mL of a 0.5M solution in THF;8.95 mmol). The ice bath was then removed and the reaction was warmed to65° C. After 4 h at 65° C., the reaction mixture was cooled to 0° C. anda solution of sodium perborate tetrahydrate (2.50 g, 16.3 mmol) in water(10 mL) was added. The reaction was then warmed to rt and stirred at rtfor 18 h; water was then added. The aqueous layer was extracted withEtOAc (2×20 mL). The combined organic extracts were washed with brine,dried (MgSO₄) and concentrated in vacuo. The crude product waschromatographed (120 g Redisep® SiO₂ column; continuous gradient from0-100% EtOAc in Hex) to afford the title compound as a colorless oil(0.37 g, 24%). LC-MS, [M+H]⁺=375.1. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d,J=8.6 Hz, 1H), 7.30-7.25 (m, 1H), 6.71-6.42 (m, 1H), 4.74-4.68 (m, 1H),4.06-3.98 (m, 5H), 3.70 (s, 3H), 3.26 (td, J=5.6, 1.4 Hz, 2H), 2.83 (tt,J=10.3, 3.9 Hz, 1H), 2.51 (s, 3H), 2.14 (dt, J=13.9, 4.3 Hz, 1H),2.02-1.87 (m, 3H), 1.82-1.56 (m, 4H).

241D. Methyl(1S,3S)-3-((2-methyl-6-(1-methyl-5-(2-(((4-nitrophenoxy)carbonyl)oxy)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of Example 241C (370 mg, 0.988 mmol) and 4-nitrophenylchloroformate (299 mg, 1.48 mmol) in THF (9.9 mL) was added pyridine(0.24 mL, 2.96 mmol). The reaction mixture was stirred at rt for 3 h,then was concentrated in vacuo. The crude product was chromatographed(120 g Redisep® SiO₂ column; continuous gradient from 0-100% EtOAc inHex) to afford the title compound as a white solid (387 mg, 72.6%).LC-MS, [M+H]⁺=540.1. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J=9.4 Hz, 2H),8.03 (d, J=8.5 Hz, 1H), 7.34 (d, J=9.4 Hz, 2H), 7.24 (d, J=8.5 Hz, 1H),4.75-4.69 (m, 3H), 4.14 (s, 3H), 3.72 (s, 3H), 3.66 (t, J=6.3 Hz, 2H),2.89-2.83 (m, 1H), 2.50 (s, 3H), 2.17 (br d, J=14.0 Hz, 1H), 2.04-1.89(m, 3H), 1.87-1.72 (m, 1H), 1.70-1.59 (m, 3H).

Example 241

To a solution of Example 241D (11 mg, 0.020 mmol) and iPr₂NEt (7.1 μl,0.041 mmol) in THF (1 mL) was added 1-cyclobutyl-N-methylmethanamine(2.0 mg, 0.020 mmol). The reaction was stirred at rt for 1 h. Water (0.5mL) was added, followed by aq. LiOH·H₂O (0.05 mL of a 2N solution, 0.10mmol). The reaction was stirred at rt for 18 h, then was acidified with1N aq. HCl to pH ˜4 and extracted with EtOAc (3×5 mL). The combinedorganic extracts were washed with brine, dried (MgSO₄) and concentratedin vacuo. The crude material was purified by preparative HPLC (Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN: waterwith 10 mM NH₄OAc; Mobile Phase B: 95:5 MeCN: water with 10 mM NH₄OAc;continuous gradient: 15-55% B over 25 min, then a 4-min hold at 100% B;Flow: 20 mL/min). Fractions containing the desired product were combinedand dried via centrifugal evaporation to afford the title compound (5.7mg, 58.7%). LC-MS, [M+H]⁺=486.0. ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br s,1H), 7.48 (br d, J=8.5 Hz, 1H), 4.76 (br s, 1H), 4.30 (br s, 2H), 4.02(s, 3H), 3.53 (br s, 2H), 3.21-3.11 (m, 1H), 3.03-2.93 (m, 1H), 2.71 (brs, 3H), 2.63-2.56 (m, 1H), 2.42 (s, 3H), 2.33-2.24 (m, 1H), 2.02-1.37(m, 14H). hLPA1 IC₅₀=41 nM.

The following examples were prepared according to the synthetic schemedescribed for Example 241.

Analytical & Biology Example Structure & Name Data Method 242

LC-MS, [M + H]⁺ = 460.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.47 (d, J = 8.5 Hz, 1H), 4.78 (br s, 1H), 4.30 (br s, 2H), 4.03(s, 3H), 3.56-3.46 (m, 2H), 3.11-2.85 (m, 2H), 2.76-2.61 (m, 4H), 2.43(s, 3H), 2.06-1.99 (m, 1H), 1.92-1.74 (m, 3H), 1.69-1.20 (m, 6H), 0.86-0.57 (m, 3H). hLPA1 IC₅₀ = 319 nM Example 241(1S,3S)-3-((2-Methyl-6-(1-methyl-5- (2-((methyl(propyl)carbamoyl)oxy)-ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylicacid, TFA salt 243

LC-MS, [M + H]⁺ = 486.0 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.46 (br d, J = 8.7 Hz, 1H), 4.73 (br s, 1H), 4.32 (br t, J = 6.1Hz, 2H), 4.23- 4.11 (m, 1H), 4.01 (s, 3H), 3.53 (br t, J = 6.0 Hz, 2H),2.60-2.55 (m, 4H), 2.42 (s, 3H), 1.99-1.22 (m, 16H). hLPA1 IC₅₀ = 72 nM.Example 241 (1S,3S)-3-((6-(5-(2-((Cyclopentyl-(methyl)carbamoyl)oxy)ethyl)-1- methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 244

LC-MS, [M + H]⁺ = 508.0 ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J = 8.2Hz, 1H), 7.48 (br d, J = 4.9 Hz, 1H), 7.36- 7.24 (m, 3H), 7.15 (br d, J= 5.2 Hz, 1H), 7.04 (br s, 1H), 4.74 (br s, 1H), 4.43- 4.30 (m, 3H),4.17 (br s, 1H), 4.05-3.92 (m, 3H), 3.56-3.49 (m, 2H), 2.71 (s, 3H),2.60-2.54 (m, 1H), 2.44-2.36 (m, 3H), 1.98-1.48 (m, 8H). hLPA1 IC₅₀ = 54nM. Example 241 (1S,3S)-3-((6-(5-(2-((Benzyl(methyl)-carbamoyl)oxy)ethyl)-1-methyl-1H- 1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 245

LC-MS, [M + H]⁺ = 474.2 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5Hz, 1H), 7.46 (br d, J = 8.6 Hz, 1H), 4.75 (br s, 1H),4.31 (br s, 2H),4.02 (s, 3H), 3.56- 3.47 (m, 2H), 2.93-2.55 (m, 7H), 2.43 (s, 3H),2.04-1.48 (m, 8H), 0.71 (br d, J = 10.8 Hz, 6H). hLPA1 IC₅₀ = 69 nM.Example 241 (1S,3S)-3-((6-(5-(2-((Isobutyl-(methyl)carbamoyl)oxy)ethyl)-1- methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 246

LC-MS, [M + H]⁺ = 458.3 ¹H NMR (500 MHz, DMSO-d₆) δ 1H), 7.45 (br d, J =8.6 Hz, 1H), 4.75 (br s, 1H), 4.31 (t, J = 6.1 Hz, 2H), 4.03 (s, 3H),3.51 (br t, J = 6.0 Hz, 2H), 3.21- 2.62 (m, 5H), 2.42 (br s, 3H),2.08-1.95 (m, 1H), 1.91-1.74 (m, 3H), 1.72- 1.50 (m, 8H). hLPA1 IC₅₀ =210 nM. Example 241 (1S,3S)-3-((2-Methyl-6-(1-methyl-5-(2-((pyrrolidine-1-carbonyl)oxy)-ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylicacid, TFA salt 247

LC-MS, [M + H]⁺ = 472.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.44 (d, J = 8.6 Hz, 1H), 4.75 (br s, 1H), 4.31 (br t, J = 6.2 Hz,2H), 4.02 (s, 3H), 3.52 (br t, J = 5.7 Hz, 2H), 3.24- 3.15 (m, 1H),2.68- 2.56 (m, 4H), 2.43 (s, 3H), 2.08-1.38 (m, 14H). hLPA1 IC₅₀ = 41nM. Example 241 (1S,3S)-3-((6-(5-(2- ((Cyclobutyl(methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)- 2-methylpyridin-3-yl)oxy)cyclo-hexane-1-carboxylic acid, TFA salt 248

LCMS, [M + H]⁺ = 472.1 ¹H NMR (500 MHz, DMSO-d₆) δ 7.49 (br s, 1H), 7.01(br s, 1H), 4.75 (br s, 1H), 4.29 (br s, 2H), 4.02 (s, 3H), 3.54- 3.24(m, 2H), 3.00-2.94 (m, 2H), 2.71-2.63 (m, 2H), 2.35 (br s, 3H), 2.09-1.45 (m, 14H). hLPA1 IC₅₀ = 144 nM. Example 241(1S,3S)-3-((6-(5-(2-(((Cyclobutyl- methyl)carbamoyl)oxy)ethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, TFA salt

Example 249(1S,3S)-3-((6-(5-(3-((Benzyl(methyl)carbamoyl)oxy)propyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

249A (2-(Benzyloxy)ethyl)triphenylphosphonium bromide

Benzyl 2-bromoethyl ether (0.78 mL, 4.96 mmol) was added to a solutionof Ph₃P (1 g, 3.81 mmol) in toluene (7.63 mL) and the reaction wasstirred at 105° C. for 18 h, then was cooled to rt. Diethyl ether (50mL) was added, and the mixture was stirred for 15 min at rt; theprecipitated product was collected by filtration, rinsed with ether andair-dried to afford the title product (1.46 g, 80%) as a white solid.LC-MS, [M]⁺=397.1. ¹H NMR (500 MHz, CDCl₃) δ 7.87-7.73 (m, 9H), 7.63(td, J=7.8, 3.3 Hz, 6H), 7.27-7.19 (m, 3H), 6.92 (d, J=6.6 Hz, 2H), 4.36(dt, J=11.7, 5.7 Hz, 2H), 4.27 (s, 2H), 4.11-4.01 (m, 2H).

249B. Methyl(1S,3S)-3-((6-(5-(3-(benzyloxy)prop-1-en-1-yl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

In a sealed tube was placed Example 249A (0.116 g, 0.243 mmol), Example241A (0.058 g, 0.162 mmol), K₂CO₃ (0.067 g, 0.485 mmol), and THF (1.6mL). The reaction was stirred at 115° C. for 2 h, then was cooled to rt.The mixture was diluted with EtOAc, washed with brine, dried (MgSO₄),and concentrated in vacuo. The crude product was chromatographed (12 gRedisep® SiO₂ column, eluting with 0-100% EtOAc in Hex) to afford thetitle compound as a yellow solid (35 mg, 45%) as a mixture of cis/transisomers.

249C Methyl(1S,3S)-3-((6-(5-(3-(benzyloxy)propyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridine-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of Example 249B (35 mg, 0.073 mmol) in MeOH (20 mL) underAr was added 20% Pd(OH)₂ on carbon (10.31 mg, 0.015 mmol) and ammoniumformate (93 mg, 1.47 mmol). The reaction mixture was stirred in a sealedtube at 65° C. for 18 h, then was cooled to rt. The reaction wasfiltered through a pad of Celite®, rinsed with MeOH, and the filtratewas concentrated in vacuo. The crude material was purified bypreparative HPLC using the following conditions: Column: Sunfire PrepC18 OBD Sum 30×100 mm; Mobile Phase A: 10:90 MeCN: water with 0.1% TFA;Mobile Phase B: 90:10 MeCN: water with 0.1% TFA; Gradient: 20-100% Bover 12 min; Flow: 40 mL/min. Fractions containing the desired productwere combined and dried via centrifugal evaporation to afford the titlecompound (40 mg, 92%) as a yellow solid. LC-MS, [M+H]⁺=479.3.

249D. Methyl(1S,3S)-3-((6-(5-(3-hydroxypropyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of Example 249C (40 mg, 0.067 mmol) in EtOH (2 mL) andAcOH (1 mL) was added 10% Pd/C (7.2 mg, 6.8 μmol), and H₂ gas wasbubbled through the reaction mixture for a few minutes; the reaction wasthen stirred under H₂-balloon for 72 h. The reaction mixture wasfiltered through a pad of Celite®, rinsed with MeOH, and the combinedfiltrate/rinses were concentrated in vacuo. The crude material waspurified by preparative HPLC using the following conditions: Column:Sunfire Prep C18 OBD 5 u 30×100 mm; Mobile Phase A: 10:90 MeCN: waterwith 0.1% TFA; Mobile Phase B: 90:10 MeCN: water with 0.1% TFA;Gradient: 20-100% B over 12 min; Flow: 40 mL/min.

Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound 246D (23 mg, 68%)as a colorless solid. LC-MS, [M+H]⁺=389.2. ¹H NMR (500 MHz, CD₃OD) δ8.10-7.98 (m, 2H), 5.02-4.96 (m, 1H), 4.15 (s, 3H), 3.71 (s, 3H), 3.62(br t, J=5.6 Hz, 2H), 3.18 (br t, J=7.2 Hz, 2H), 2.91-2.83 (m, 1H), 2.71(s, 3H), 2.20-2.10 (m, 1H), 2.07-1.90 (m, 5H), 1.85-1.65 (m, 4H).

249EMethyl(1S,3S)-3-((2-methyl-6-(1-methyl-5-(3-(((4-nitrophenoxy)carbonyl)oxy)propyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of Example 249D (21 mg, 0.042 mmol) and 4-nitrophenylchloroformate (12.6 mg, 0.063 mmol) in THF (1 mL) was added pyridine (10μl, 0.13 mmol). The reaction was stirred at rt for 18 h, then wasconcentrated in vacuo. The crude product was chromatographed (4 gRedisep® SiO₂ column, eluting with 0-100% EtOAc in Hex) to afford thetitle compound (10 mg, 43%) as a white solid. LC-MS, [M+H]⁺=554.2.

Example 249

To a solution of Example 249E (10 mg, 0.018 mmol) and DIEA (6.31 μl,0.036 mmol) in THF (1 mL) was added N-methyl-1-phenylmethanamine (2.2mg, 0.018 mmol). After 1 h, water (0.5 mL) was added, followed by aq.LiOH (0.070 mL of a 2M solution, 0.139 mmol). The reaction mixture wasstirred at rt for 18 h, after which the pH was adjusted with 1N aq. HClto ˜4 and the mixture was extracted with EtOAc (3×). The combinedorganic extracts were washed with brine, dried (MgSO₄) and concentratedin vacuo. The crude material was purified by preparative HPLC using thefollowing conditions: Column: Sunfire Prep C18 OBD 5 u 30×100 mm; MobilePhase A: 10:90 MeCN: water with 0.1% TFA; Mobile Phase B: 90:10 MeCN:water with 0.1% TFA; Gradient: 20-100% B over 12 min; Flow: 40 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation, then re-purified by preparative HPLC using thefollowing conditions: Column: Sunfire Prep C18 OBD 5 u 30×100 mm; MobilePhase A: 10:90 MeOH: water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Gradient: 20-100% B over 12 min; Flow: 40 mL/min.Fractions containing the desired product were combined and dried viacentrifugal evaporation to afford the title compound (2.1 mg, 18%) as awhite solid. LC-MS, [M+H]⁺=522.3. ¹H NMR (400 MHz, 60° C., CD₃OD) δ 7.65(br d, J=8.4 Hz, 1H), 7.32 (br d, J=8.8 Hz, 1H), 7.23-7.05 (m, 5H),4.69-4.61 (m, 1H), 4.30 (s, 2H), 4.09 (t, J=5.6 Hz, 2H), 3.90 (br s,3H), 3.16-3.08 (m, 2H), 2.75-2.63 (m, 4H), 2.39 (s, 3H), 2.04-1.89 (m,3H), 1.89-1.75 (m, 3H), 1.72-1.49 (m, 4H). hLPA1 IC₅₀=122 nM.

Synthesis of Amine Intermediate for the Preparation of Example 250Intermediate 5. N-methyl-2-propoxyethan-1-amine

Intermediate 5A. N-benzyl-N-methyl-2-propoxyethan-1-amine

To a solution of 2-(benzyl(methyl)amino)ethan-1-ol (1 mL, 6.15 mmol) indry DMF (5 mL) was added 60% NaH in mineral oil (0.369 g, 9.23 mmol) at0° C. After 1 h, 1-chloropropane (0.813 mL, 9.23 mmol) was added. Thereaction mixture was stirred overnight at rt, then was quenched with icewater and extracted with EtOAc. The organic phase was washed with waterand brine, dried (Na₂SO₄) and concentrated in vacuo. The crude oilyproduct was chromatographed (24 g SiO₂; elution with EtOAc/Hexane(continuous gradient from 0% to 100% over 10 min)) to give the freeamine as an oil. This oil was treated with 2.0 M HCl in ether to giveN-benzyl-N-methyl-2-propoxyethan-1-amine HCl salt (1.2 g, 4.92 mmol, 80%yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.67-7.61 (m, 2H),7.47-7.43 (m, 3H), 4.34-4.20 (m, 2H), 4.04-3.93 (m, 2H), 3.46 (t, J=6.6Hz, 2H), 3.34-3.27 (m, 1H), 3.14-3.06 (m, 1H), 2.74 (d, J=5.1 Hz, 3H),1.65-1.59 (m, 2H), 0.93 (t, J=7.4 Hz, 3H)

Intermediate 5

A mixture of Intermediate 5A (1.2 g, 4.92 mmol) and 20% Pd(OH)2-C (0.346g, 2.461 mmol) in EtOH (5 mL) was stirred at 60° C. under 1 atmosphereH₂ for 2 h, then was filtered and concentrated in vacuo to provide thetitle intermediate as the HCl salt (0.72 g, 4.69 mmol, 95% yield) as awhite solid. ¹H NMR (500 MHz, CDCl₃) δ 9.41 (br s, 2H), 3.81 (t, J=4.8Hz, 2H), 3.44 (t, J=6.6 Hz, 2H), 3.24-3.11 (m, 2H), 2.77 (br t, J=5.0Hz, 3H), 1.60 (sxt, J=7.1 Hz, 2H), 0.90 (t, J=7.4 Hz, 3H).

Synthesis of Amine Intermediate 6 for Examples 254 & 255 Intermediate 6.2-fluoro-N-methylbutan-1-amine

Intermediate 6A. 1-(benzyl(methyl)amino)butan-2-ol

A solution of N-methyl-1-phenylmethanamine (6.09 mL, 46.4 mmol) and1,2-epoxybutane (1.0 mL, 11.6 mmol) in EtOH (50 mL) was stirred underreflux for 8 h, then was cooled to rt and concentrated in vacuo. Thecrude residue was chromatographed (80 g SiO₂; elution with MeOH/DCM(continuous gradient from 0% to 10% over 20 min) to give the titlecompound (500 mg, 2.59 mmol, 22.3% yield) as a clear oil. ¹H NMR (500MHz, CDCl₃) δ 7.35-7.24 (m, 5H), 3.72-3.41 (m, 4H), 2.42-2.32 (m, 2H),2.23 (s, 3H), 1.50-1.36 (m, 2H), 0.97 (t, J=7.6 Hz, 3H); [M+H]⁺=194.3

Intermediate 6B. N-benzyl-2-fluoro-N-methylbutan-1-amine

DAST (0.697 mL in THF, 5.28 mmol) was added to a solution ofIntermediate 6A (0.51 g, 2.64 mmol) in DCM (3 mL) at −78° C. and thereaction was stirred for 5 h at −78° C. and for 18 h at rt. Volatileswere concentrated in vacuo and the residue was carefully quenched withwater (2 mL). The aqueous solution containing product was purified byprepHPLC (Sunfire C18 30×100 mm-regenerated column; detection at 220 nm;flow rate=40 mL/min; continuous gradient from 0% B to 100% B over 10min+2 min hold time at 100% B, where A=90:10:0.1 H₂O:MeCN:TFA andB=90:10:0.1 MeCN:H₂O:TFA) and appropriate fractions were concentrated toobtain an oil. The residue was treated with 2.0 M HCl in ether (3.61 mL,7.22 mmol) to give the HCl salt of the title compound (0.22 g, 1.127mmol, 42.7% yield) as a clear oil. ¹H NMR (500 MHz, CD₃OD) δ 7.54 (s,5H), 5.12-4.91 (m, 1H), 4.68-4.22 (m, 2H), 3.56-3.41 (m, 2H), 3.01-2.83(m, 3H), 1.84-1.60 (m, 2H), 1.06 (q, J=7.7 Hz, 3H); ¹⁹F NMR (471 MHz,METHANOL-d₄) 6-186.78 (s), −188.25(s); [M+H]⁺=196.3

Intermediate 6

A mixture of Intermediate 6B (0.22 g, 0.95 mmol) and 20% Pd(OH)₂—C(0.067g, 0.475 mmol) in EtOH (5 mL) was stirred at 60° C. under 1 atmosphereof H₂ for 2 h. The mixture was filtered and concentrated in vacuo toprovide the title compound as the HCl salt (0.099 g, 9.41 mmol, 99%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.06-9.40 (m, 2H),5.34-4.94 (m, 1H), 3.38-3.02 (m, 2H), 2.81 (br s, 3H), 1.75 (br d, J=1.5Hz, 2H), 1.04 (br t, J=6.2 Hz, 3H); ¹⁹F NMR (377 MHz, CDCl₃) δ: −185.22(br s, F).

Intermediate 7. 4-fluoro-N-methylpentan-1-amine (for the Synthesis ofExample 256)

7A. N-benzyl-4-hydroxy-N-methylpentanamide

N-methyl-1-phenylmethanamine (5.78 mL, 44.9 mmol) was added to a mixtureof 5-methyl dihydrofuran-2(3H)-one (1.426 mL, 14.98 mmol) and toluene(20 mL), and NaOMe solution (sodium (1.033 g, 44.9 mmol) added to MeOH(15 mL)) was added dropwise at 20 to 30° C., followed by stirring for 18h at rt. The reaction was quenched by addition of ice water (20 mL) andHOAc (3.43 mL, 60 mmol) was added dropwise. The aqueous layer wasextracted with EtOAc (2×20 mL). The combined organic extracts werewashed with water and concentrated in vacuo. The crude oily product waschromatographed (40 g SiO₂; elution with EtOAc/Hexane (continuousgradient from 0% to 100% over 10 min)) to give the title compound (1.5g, 6.78 mmol, 45.2% yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ7.41-7.13 (m, 5H), 4.63-4.53 (m, 2H), 3.85 (dddd, J=14.0, 8.0, 6.2, 4.2Hz, 1H), 3.02 (dd, J=7.4, 4.5 Hz, 1H), 2.98-2.91 (m, 3H), 2.66-2.45 (m,2H), 1.97-1.70 (m, 2H), 1.21 (dd, J=17.6, 6.4 Hz, 3H)); [M+H]⁺=222.2.

7B. 5-(benzyl(methyl)amino)pentan-2-ol

Intermediate 7A (1.5 g, 6.78 mmol) was added to a suspension of LAH(4.07 mL of a 2.0 M solution in THF; 8.13 mmol) in THF (50 mL). Themixture was heated at reflux for 18 h, then was cooled to 0° C. Brine(˜1 mL) was carefully added until no more gas was generated. The solidswere filtered off, and the filtrate was concentrated in vacuo. The cruderesidue was chromatographed (12 g SiO₂; elution with MeOH/DCM(continuous gradient from 0% to 10% over 20 min) to give the titlecompound (1.35 g, 6.51 mmol, 96% yield) as a clear oil. ¹H NMR (500 MHz,CDCl₃) δ 7.40-7.25 (m, 5H), 3.84-3.73 (m, 1H), 3.56 (q, J=12.7 Hz, 2H),2.59-2.51 (m, 1H), 2.49-2.39 (m, 1H), 2.18 (s, 3H), 1.82-1.67 (m, 3H),1.50-1.40 (m, 1H), 1.22 (d, J=6.3 Hz, 3H); [M+H]⁺=208.3.

7C. N-benzyl-4-fluoro-N-methylpentan-1-amine

DAST (1.03 mL in THF, 7.81 mmol) was added to a solution of Intermediate7B (0.81 g, 3.91 mmol) in DCM (3 mL) at −78° C. and the reaction wasstirred for 5 h at −78° C. and for 18 h at rt. The reaction wasconcentrated in vacuo and carefully quenched with water (2 mL). Theaqueous solution was purified by preparative HPLC (Sunfire C18 30×100mm-regenerated column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 0% B to 100% B over 10 min+2 min hold time at100% B, where A=90:10:0.1 H₂O:MeCN:TFA and B=90:10:0.1 MeCN:H₂O:TFA) andappropriate fractions were concentrated to give an oil. The residue wastreated with 2.0 M HCl in ether (3.61 mL, 7.22 mmol) to give the titlecompound as the HCl salt (0.12 g, 0.488 mmol, 12.50% yield) as a clearoil. ¹H NMR (400 MHz, CDCl₃) δ 12.21 (br s, 1H), 7.62 (br s, 2H),7.50-7.41 (m, 3H), 4.80-4.55 (m, 1H), 4.32-4.15 (m, 2H), 3.23-2.83 (m,2H), 2.81-2.64 (m, 3H), 2.21-1.94 (m, 2H), 1.78-1.55 (m, 2H), 1.40-1.27(m, 3H); ¹⁹F NMR (377 MHz, CDCl₃) δ −173.65 (d, J=38.9 Hz, F);[M+H]⁺=210.2

Intermediate 7

A mixture of Intermediate 7C (0.12 g, 0.488 mmol) and 20%Pd(OH)₂—C(0.034 g, 0.24 mmol) in EtOH (5 mL) was stirred at 60° C. under1 atmosphere H₂ for 2 h. The reaction was filtered and concentrated invacuo to provide the title compound as the HCl salt (0.05 g, 0.321 mmol,65.8% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 9.51 (br s,2H), 4.83-4.62 (m, 1H), 3.01 (br s, 2H), 2.70 (br s, 3H), 2.13-1.94 (m,2H), 1.81-1.65 (m, 2H), 1.41-1.29 (m, 3H); ¹⁹F NMR (471 MHz; CDCl₃) δ−173.53 (s, 1F).

Example Structure & Name Analytical & Biology Data Method 250

LCMS; [M + H]⁺ = 490.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (br s, 1H),7.47 (d, J = 8.6 Hz, 1H), 5.66 (br s, 2H), 4.77 (br s, 1H), 4.10 (s,3H), 2.83 (br s, 3H), 2.71-2.61 (m, 1H), 2.43 (s, 3H), 2.08- 1.98 (m,1H), 1.91-1.76 (m, 3H), 1.72-1.34 (m, 6H), 0.79 (br s, 3H), 6 protonsare in water suppression area LPA1 IC₅₀ = 314 nM Example 1(1S,3S)-3-((2-methyl-6-(1-methyl-5- (((methyl(2-propoxyethyl)carbamoyl)oxy)methyl)- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 251

LCMS; [M + H]⁺ = 458.1; ¹H NMR (500 MHz, CDCl₃) δ 8.64 (d, J = 2.5 Hz,1H), 8.24 (d, J = 8.8 Hz, 1H), 7.89-7.79 (m, 1H), 5.54 (s, 2H), 4.84 (brs, 1H), 4.23 (br s, 3H), 3.23- 3.15 (m, 1H), 3.14-2.98 (m, 1H), 2.94 (brs, 4H), 2.19-2.01 (m, 2H), 1.98- 1.75 (m, 5H), 1.73-1.61 (m, 1H), 1.03(br s, 3H), 0.70-0.51 (m, 2H), 0.42- 0.22 (m, 2H) LPA1 IC₅₀ = 27 nMExample 3 (1S,3S)-3-((6-(1-methyl-5- (((methyl(((1R,2R)-2-methylcyclopropyl)methyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 252

LCMS; [M + H]⁺ = 458.1; ¹H NMR (500 MHz, CDCl₃) δ 8.64 (d, J = 1.9 Hz,1H), 8.23 (d, J = 8.8 Hz, 1H), 7.82 (br d, J = 8.0 Hz, 1H), 5.54 (s,2H), 4.84 (br s, 1H), 4.23 (br s, 3H), 3.24- 3.14 (m, 1H), 3.14-2.97 (m,1H), 2.93 (br s, 4H), 2.19-2.00 (m, 2H), 1.98- 1.61 (m, 6H), 1.02 (br s,3H), 0.69-0.50 (m, 2H), 0.42-0.20 (m, 2H) LPA1 IC₅₀ = 29 nM Example 3(1S,3S)-3-((6-(1-methyl-5- (((methyl(((1S,2S)-2-methylcyclopropyl)methyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 253

LCMS; [M + H]⁺ = 478.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J = 8.5Hz, 1H), 7.47 (br d, J = 8.6 Hz, 1H), 5.67 (br s, 4H), 4.77 (br s, 2H),4.10 (s, 4H), 2.86 (br s, 2H), 2.65 (br t, J = 10.1 Hz, 1H), 2.42 (s,3H), 2.08-1.99 (m, 1H), 1.91-1.75 (m, 3H), 1.73-1.44 (m, 4H), 1.37-0.97(m, 6H) 3 protons are in water suppression area LPA1 IC₅₀ = 134 nMExample 1 (1S,3S)-3-((6-(5-((((2-fluoro-2-methylpropyl)(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy) cyclohexane-1-carboxylic acid254

LCMS; [M + H]⁺ = 479.1; ¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (s, 1H),5.71-5.48 (m, 2H), 5.39 (br s, 1H), 4.73-4.21 (m, 1H), 4.11 (s, 3H),3.57- 3.19 (m, 2H), 2.90-2.74 (m, 3H), 2.64 (br t, J = 11.1 Hz, 1H),2.45 (s, 3H), 2.19- 2.04 (m, 1H), 1.96-1.72 (m, 3H), 1.70-1.24 (m, 6H),0.97-0.60 (m, 3H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −73.42 (br s, TFA),−185.33 (br d, J = 97.1 Hz, F) LPA1 IC₅₀ = 132 nM(1S,3S)-3-((5-(5-((((2- fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-3-methylpyrazin-2-yl)oxy)cyclohexane-1-carboxylic acid; mixture of diastereomers 255

LCMS; [M + H]⁺ = 478.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (br s, 1H),7.47 (br d, J = 8.2 Hz, 1H), 5.76-5.51 (m, 2H), 4.77 (br s, 1H),4.69-4.20 (m, 1H), 4.09 (s, 3H), 3.60- 3.20 (m, 2H), 2.94-2.73 (m, 3H),2.62 (br s, 1H), 2.40 (br s, 3H), 2.07-1.19 (m, 10H), 0.98-0.55 (m, 3H);¹⁹F NMR (471 MHz, DMSO-d₆) δ −73.54 (s, TFA), −185.49 (s) LPA1 IC₅₀ = 57nM Example 1 (1S,3S)-3-((6-(5-((((2- fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid; mixture of diastereomers 256

LCMS; [M + H]⁺ = 492.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5Hz, 1H), 7.45 (br d, J = 8.5 Hz, 1H), 5.62 (br d, J = 13.7 Hz, 2H),4.85-4.29 (m, 2H), 4.08 (s, 3H), 3.25- 3.03 (m, 2H), 2.83-2.68 (m, 3H),2.62 (br t, J = 10.2 Hz, 1H), 2.40 (s, 3H), 1.99 (br d, J = 13.7 Hz,1H), 1.90- 0.97 (m, 11H), 0.84 (br t, J = 7.2 Hz, 3H); ¹⁹F NMR (471 MHz,DMSO-d₆) δ −73.75 (s, TFA), −170.59 (br d, J = 65.9 Hz, F) LPA1 IC₅₀ =17 nM Example 1 (1S,3S)-3-((6-(5-((((4-fluoropentyl)(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3- yl)oxy)cyclohexane-1-carboxylic acid

Example 257(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1R,2R)-2-methylcyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

257A. (E)-N-benzylbut-2-enamide

EDC (36.7 g, 192 mmol) was added portionwise to a solution of crotonicacid (15.0 g, 174 mmol), benzyl amine (21.0 mL, 192 mmol) and DIPEA(33.5 mL, 192 mmol) in DCM (300 mL). The reaction mixture was stirredovernight and then poured onto 10% aq. KHSO₄ (250 mL) and extracted withEtOAc (100 mL). The organic layer was washed once again with 10% aq.KHSO₄ followed by brine (150 mL), dried (Na₂SO₄) and concentrated invacuo to give the title compound as a white solid (25 g, 143 mmol, 82%yield). [M+H]⁺=176.2; ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.20 (m, 5H),6.98-6.82 (m, 1H), 5.84 (br dd, J=15.1, 1.7 Hz, 2H), 4.52 (d, J=5.8 Hz,2H), 1.87 (dd, J=6.9, 1.7 Hz, 3H)

257B. N-benzyl-2-methylcyclopropanecarboxamide

In an Erlenmeyer flask containing Et₂O (50 mL) and aq. 40% KOH (5 mL)was added N-methyl-N′-nitro-N-nitrosoguanidine (504 mg, 3.42 mmol)portionwise (with vigorous stirring) over 15 min at 0° C. Upon completeaddition, stirring was stopped and the aqueous layer was separated. Theether layer was dried with KOH pellets and allowed to stand for 5 min,then decanted into a third flask with KOH pellets and then poured onto aTHF solution (2 mL) containing Example 257A (300 mg, 1.712 mmol).Pd(OAc)₂ (3.84 mg, 0.017 mmol) was subsequently added and the reactionallowed to warm to rt and stirred for 1 h at rt. The reaction wasconcentrated in vacuo, and the crude oil was chromatographed (12 g SiO₂;elution with EtOAc/Hexane (continuous gradient from 0% to 50% over 20min) to give the title compound (310 mg, 1.61 mmol, 94% yield) as awhite solid. [M+H]⁺=190.2; ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.26 (m, 5H),5.82 (br s, 1H), 4.44 (dd, J=5.6, 2.3 Hz, 2H), 1.46-1.32 (m, 1H),1.22-1.15 (m, 1H), 1.12-1.03 (m, 4H), 0.57 (ddd, J=7.9, 6.2, 3.7 Hz, 1H)

257C (1R,2R)-N-benzyl-2-methylcyclopropane-1-carboxamide and 257D(1S,2S)-N-benzyl-2-methylcyclopropane-1-carboxamide

Example 257B (2.0 g, 10.6 mmol) was separated by chiral preparative HPLC(Instrument: Berger MG II (CTR-L409-PSFC1), Column: Chiralpak ID, 21×250mm, 5 micron, Mobile Phase: 15% IPA/85% CO2, Flow Conditions: 45 mL/min,150 Bar, 40° C., Detector Wavelength: 220 nm, Injection Details: 0.25 mLof an −200 mg/mL in IPA) to give Example 257C (0.9 g, 4.76 mmol, 45.0%yield, 99.0% ee) and Example 257D (0.9 g, 4.76 mmol, 45.0% yield, 99.0%ee) as white solids. The absolute stereochemistry of these two isomerswas previously determined in the literature reference Bioorg. Med. Chem.Lett. 2007, 17, 1788.

257E. N-benzyl-1-((1R,2R)-2-methylcyclopropyl)methanamine

To a solution of Example 257C (0.90 g, 4.76 mmol) in THF (50 mL) wasadded BH₃·THF (23.8 mL of a 1M solution in THF, 23.8 mmol) dropwise.Upon completion of the addition (10 min), the mixture was heated atreflux for 5 h, then cooled to rt and quenched via successive additionof MeOH (2 mL) and 1N aq. HCl dropwise (10 mL). The resulting solutionwas stirred at 50° C. for 1 h and then partitioned between water andEt₂O (50 mL each). The aqueous layer was neutralized with 7N aq. KOH andextracted with DCM (3×10 mL). The organic layers were dried (Na₂SO₄) andconcentrated in vacuo. The oily product was diluted with EtOAc andtreated with HCl gas. The resulting solids were filtered, washed withhexane and dried to give the title compound (HCl salt; 0.9 g, 4.25 mmol,89% yield) as a white solid. [M+H]⁺=176.2; ¹H NMR (400 MHz, CD₃OD) δ7.56-7.43 (m, 5H), 4.21 (s, 2H), 3.02-2.90 (m, 2H), 1.12 (d, J=5.5 Hz,3H), 0.93-0.73 (m, 2H), 0.59 (dt, J=8.0, 5.0 Hz, 1H), 0.50 (dt, J=7.8,5.3 Hz, 1H)

257F. N-benzyl-N-methyl-1-((1R,2R)-2-methylcyclopropyl)methanamine

A solution of Example 257E (0.90 g, 5.13 mmol), 36% aq. formaldehydesolution (1.97 mL, 25.7 mmol), and HOAc (3 mL, 52.4 mmol) in MeOH (10mL) was stirred at rt for 5 min. NaBH(OAc)₃ (2.177 g, 10.27 mmol) wasthen added. The reaction mixture was stirred at rt for 20 min and thenconcentrated in vacuo and the residue was partitioned between DCM (20mL) and 1N NaOH (50 mL). The organic layer was dried (MgSO₄) andconcentrated in vacuo. The residue was treated with 2.0 M HCl in ether(3 mL, 6.0 mmol) to give the title compound (HCl salt; 0.97 g, 4.30mmol, 84% yield) as a white solid. [M+H]⁺=176.2; ¹H NMR (400 MHz, CD₃OD)δ 7.55-7.51 (m, 5H), 4.49 (dd, J=13.0, 7.3 Hz, 1H), 4.24 (br d, J=13.2Hz, 1H), 3.22-3.14 (m, 1H), 3.02 (dt, J=13.3, 7.8 Hz, 1H), 2.85 (d,J=5.9 Hz, 3H), 1.15 (d, J=5.7 Hz, 3H), 0.94-0.79 (m, 2H), 0.66-0.53 (m,2H)

257G. N-methyl-1-((1R,2R)-2-methylcyclopropyl)methanamine

A mixture of Example 257F HCl salt (0.97 g, 4.30 mmol) and 20% Pd(OH)₂—C(0.1 g, 0.712 mmol) in EtOH (40 mL) was stirred at 60° C. under 1atmosphere of H₂ for 2 h. The reaction was filtered and concentrated invacuo to provide the title compound (HCl salt, 0.54 g, 3.98 mmol, 93%yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 2.91 (d, J=7.3 Hz,2H), 2.71 (s, 3H), 1.12 (d, J=5.9 Hz, 3H), 0.92-0.75 (m, 2H), 0.59 (dt,J=8.4, 4.9 Hz, 1H), 0.48 (dt, J=8.0, 5.1 Hz, 1H)

Example 257

To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1 mL) was addedExample 257G HCl salt (7.4 mg, 0.054 mmol) and DIPEA (0.028 mL, 0.163mmol). The reaction mixture was stirred at rt for 2 h and thenconcentrated in vacuo. The residue was stirred with 1.0 M aq. NaOH (0.54mL, 0.54 mmol) in THF (1 mL)/MeOH (0.2 mL) at rt for 18 h, thenconcentrated in vacuo and purified by preparative HPLC (Xbridge C18 5 uOBD 19×100 mm column; detection at 220 nm; flow rate=20 mL/min;continuous gradient from 15% B to 100% B over 10 min+2 min hold time at100% B, where A=90:10:0.1 H₂O:MeCN:TFA and B=90:10:0.1 MeCN:H₂O:TFA) togive the title compound (TFA salt; 26 mg, 0.044 mmol, 81% yield) as ayellowish oil. [M+H]⁺=472.1; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=8.8Hz, 1H), 7.66 (br t, J=9.9 Hz, 1H), 5.67-5.53 (m, 2H), 4.80 (br s, 1H),4.18 (s, 3H), 3.28-2.91 (m, 5H), 2.86 (br s, 1H), 2.66 (s, 3H),2.15-1.56 (m, 8H), 1.01 (br dd, J=12.1, 5.1 Hz, 3H), 0.72-0.46 (m, 2H),0.43-0.13 (m, 2H); ¹⁹F NMR (377 MHz, CDCl₃) δ −75.88 (s, TFA). hLPA1IC₅₀=18 nM

Example 258(1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1S,2S)-2-methylcyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

258A. N-methyl-1-((1S,2S)-2-methylcyclopropyl)methanamine

The same synthetic sequence to prepare Example 257G (from Example 257C)was used to prepare Example 258A from Example 257D (HCl salt; 0.53 g,3.91 mmol, 91% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 2.91(d, J=7.3 Hz, 2H), 2.75-2.70 (m, 3H), 1.12 (d, J=5.7 Hz, 3H), 0.95-0.76(m, 2H), 0.59 (dt, J=8.5, 4.9 Hz, 1H), 0.48 (dt, J=8.2, 5.1 Hz, 1H)

Example 258

To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1 mL) addedExample 258A HCl salt (7.35 mg, 0.054 mmol) and DIPEA (0.028 mL, 0.163mmol). The reaction mixture was stirred at rt for 2 h, then wasconcentrated in vacuo. The residue was stirred with 1.0 M aq. NaOH(0.542 mL, 0.542 mmol) in THF (1 mL)/MeOH (0.2 mL) at rt for 18 h andthen purified by preparative HPLC (Xbridge C18 5 u OBD 19×100 mm column;detection at 220 nm; flow rate=20 mL/min; continuous gradient from 30% Bto 100% B over 10 min+2 min hold time at 100% B, where A=90:10:0.1H₂O:MeCN:TFA and B=90:10:0.1 MeCN:H₂O:TFA) to give the title compound(TFA salt, 27 mg, 0.046 mmol, 84% yield) as a yellowish oil.[M+H]⁺=472.1; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=8.8 Hz, 1H), 7.63 (brt, J=9.6 Hz, 1H), 5.72-5.51 (m, 2H), 4.79 (br d, J=3.1 Hz, 1H), 4.18 (s,3H), 3.29-2.80 (m, 6H), 2.65 (s, 3H), 2.11-1.98 (m, 2H), 1.97-1.56 (m,6H), 1.01 (br dd, J=13.4, 5.1 Hz, 3H), 0.69-0.16 (m, 4H). hLPA1 IC₅₀=19nM

Example 259(1S,3S)-3-((6-(5-((((2,2-difluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

259A. N-benzyl-2,2-difluoro-N-methylpropan-1-amine

To a solution of 1-(benzyl(methyl)amino)propan-2-one (1.28 g, 7.22 mmol)and DAST (2.86 mL, 21.66 mmol) in DCM (12 ml) was added CsF (0.329 g,2.166 mmol) portionwise, followed by a few drops of TFA at rt. Thereaction mixture was stirred for 18 h at rt, then was quenched with satdaq. NaHCO₃. The aqueous layer was extracted with DCM (50 mL×3). Thecombined organic extracts were washed with water, brine, dried (MgSO₄)and concentrated in vacuo. The crude oily product was chromatographed(12 g SiO₂; elution with EtOAc/Hexane (continuous gradient from 0% to50% over 10 min) and then further purified by preparative HPLC to give aclear oil. This material was treated with 2.0 M HCl in ether (3.61 mL,7.22 mmol) to give the title compound (HCl salt, 334 mg, 1.417 mmol,19.6% yield) as a white solid. [M+H]⁺=482.3; ¹H NMR (400 MHz, CDCl₃) δ7.68 (dt, J=3.8, 2.8 Hz, 2H), 7.55-7.38 (m, 3H), 4.56-4.18 (m, 2H),3.65-3.15 (m, 2H), 2.94 (s, 3H), 1.80 (t, J=19.3 Hz, 3H); ¹⁹F NMR (377MHz, CDCl₃) δ −87.77 to −91.55 (m, F)

259B. 2,2-difluoro-N-methylpropan-1-amine

A mixture of Example 259A (HCl salt; 0.33 g, 1.40 mmol) and 20%Pd(OH)₂—C (0.10 g, 0.712 mmol) in EtOH (40 mL) was stirred at 60° C.under 1 atmosphere H₂ for 2 h. Filtration and concentration in vacuoprovided 2,2-difluoro-N-methylpropan-1-amine (HCl salt, 200 mg, 1.37mmol, 98% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ 3.63 (t, J=14.9 Hz, 2H), 2.81 (s, 3H), 1.79(t, J=19.1 Hz, 3H); ¹⁹F NMR (471 MHz, CD₃OD) δ −98.01 (s)

Example 259

To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1 mL) addedExample 259B (HCl salt; 15.78 mg, 0.108 mmol) and DIPEA (0.047 mL, 0.271mmol). The reaction mixture was stirred at 50° C. for 18 h and thenconcentrated in vacuo. The residue was stirred with 1.0 M aq. NaOH(0.271 mL, 0.271 mmol) in THF (1 mL)/MeOH (0.2 mL) at rt for 18 h andthen purified by preparative LC/MS (Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 MeCN:H₂O with 10-mM NH₄OAc; Mobile PhaseB: 95:5 MeCN:H₂O with 10-mM NH₄OAc; Gradient: 15-55% B over 20 min, thena 4-min hold at 100% B; Flow: 20 mL/min) to give the title compound (TFAsalt; 9.3 mg, 0.015 mmol, 27.4% yield) as a yellowish oil. [M+H]⁺=482.3;¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (br d, J=7.9 Hz, 1H), 7.49 (br d, J=8.5Hz, 1H), 5.70 (br d, J=18.3 Hz, 2H), 4.79 (br s, 1H), 4.11 (br s, 3H),3.76-3.52 (m, 1H), 2.95-2.78 (m, 3H), 2.64 (br t, J=10.4 Hz, 1H), 2.42(s, 3H), 2.03 (br d, J=13.7 Hz, 1H), 1.92-1.74 (m, 3H), 1.69-1.34 (m,8H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −73.67 (s, TFA), −93.07 (br d, J=64.2Hz). hLPA1 IC₅₀=134 nM

Example 260(1S,3S)-3-((6-(5-((((3-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

260A. 4-(benzyl(methyl)amino)butan-2-one

A mixture of N-methyl-1-phenylmethanamine (2.57 mL, 20 mmol),paraformaldehyde (0.901 g, 30.0 mmol) and conc. HCl (1.67 mL, 20.0 mmol)in iPrOH (2 mL) and acetone (50 mL) was stirred under reflux overnightand then concentrated in vacuo. The residue was diluted with water,basified to pH 14 with 1 N aq. NaOH solution (33.4 mL, 33.4 mmol) andextracted with ether. The organic phase was dried (Na₂SO₄) andconcentrated in vacuo to give the title compound (4.0 g, 20.9 mmol, 94%yield), which was used directly in the next reaction. [M+H]⁺=192.2; ¹HNMR (400 MHz, CDCl₃) δ 7.34-7.22 (m, 5H), 3.49 (s, 2H), 2.74-2.67 (m,2H), 2.66-2.58 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H)

260B. 4-(benzyl(methyl)amino)butan-2-ol

NaBH₄ (2.37 g, 62.7 mmol) was added to a solution of Example 260A (4.0g, 20.9 mmol) in MeOH (90 mL) at 0° C. under N₂. The reaction mixturewas stirred for 1 h at 0° C.; water was then added at 0° C. and themixture was concentrated in vacuo. The residue was dissolved in EtOAc,washed with water, dried (Na₂SO₄) and concentrated in vacuo. The residuewas chromatographed (SiO₂; elution with isocratic 10% EtOH/CHCl₃) togive the title compound (3.5 g, 18.11 mmol, 87% yield) as a lightyellowish oil. [M+H]⁺=194.2; ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.27 (m,5H), 3.99-3.86 (m, 1H), 3.72-3.31 (m, 2H), 2.76 (td, J=12.0, 3.3 Hz,1H), 2.59-2.48 (m, 1H), 2.22 (s, 3H), 1.72-1.61 (m, 1H), 1.54-1.45 (m,1H), 1.15 (d, J=6.2 Hz, 3H)

260C. N-benzyl-3-fluoro-N-methylbutan-1-amine

DAST (1.367 mL, 10.35 mmol) was added to a solution of Example 260B (1.0g, 5.17 mmol) in DCM (5 mL) at −78° C. and the reaction was stirred for5 h at −78° C. and 18 h at rt, after which it was quenched with sat. aq.NaHCO₃ (50 mL). The aqueous layer was extracted with DCM (20 mL×3), andthe combined organic extracts were dried (MgSO₄) and concentrated invacuo. The crude oil was purified by preparative HPLC (Sunfire C1830×100 mm-regenerated column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 0% B to 100% B over 10 min+2 min hold time at100% B, where A=90:10:0.1 H₂O:MeCN:TFA and B=90:10:0.1 MeCN:H₂O:TFA) andappropriate fractions were concentrated in vacuo to give an oil. Thisproduct was treated with 2.0 M HCl in ether (3.61 mL, 7.22 mmol) to givethe title compound (HCl salt; 0.15 g, 0.647 mmol, 12.5% yield) as awhite solid. [M+H]⁺=196.2; ¹H NMR (400 MHz, CDCl₃) δ 7.69-7.54 (m, 2H),7.50-7.34 (m, 3H), 4.97-4.57 (m, 1H), 4.39-3.96 (m, 2H), 3.38-3.21 (m,1H), 3.08-2.88 (m, 1H), 2.77-2.64 (m, 3H), 2.57-1.96 (m, 2H), 1.54-1.29(m, 3H); ¹⁹F NMR (377 MHz, CDCl₃) δ −176.04 (s), −176.11 (s)

260D

A mixture of Example 260C (HCl salt; 0.15 g, 0.647 mmol) and 20%Pd(OH)₂—C (0.045 g, 0.324 mmol) in EtOH (5 mL) was stirred at 60° C.under 1 atmosphere H₂ for 2 h. Filtration and concentration in vacuoprovided the title compound (HCl salt; 0.075 g, 0.530 mmol, 82% yield)as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 5.01-4.71 (m, 1H), 3.13 (br s, 2H), 2.72 (brs, 3H), 2.33-2.06 (m, 2H), 1.53-1.25 (m, 3H); ¹⁹F NMR (377 MHz, CDCl₃) δ−175.47 (s, 1F)

Example 260

To a solution of Example 1F (30 mg, 0.054 mmol) in DCM (1 mL) was addedExample 260D (HCl salt; 15.4 mg, 0.11 mmol) and DIPEA (0.047 mL, 0.271mmol). The reaction mixture was stirred at rt for 1 h, then wasconcentrated in vacuo. The residue was stirred with 1.0 M aq. NaOH(0.271 mL, 0.271 mmol) in THF (1 mL)/MeOH (0.2 mL) at rt for 18 h andthen was purified by preparative HPLC (Sunfire C18 30×100 mm-regeneratedcolumn; detection at 220 nm; flow rate=40 mL/min; continuous gradientfrom 30% B to 100% B over 10 min+2 min hold time at 100% B, whereA=90:10:0.1 H₂O:MeCN:TFA and B=90:10:0.1 MeCN:H₂O: TFA) to give thetitle compound (TFA salt; 24 mg, 0.040 mmol, 73.4% yield) as a yellowishoil.

[M+H]⁺=478.1; ¹H NMR (500 MHz, CDCl₃) δ 8.18 (br d, J=8.5 Hz, 1H), 8.00(br d, J=8.0 Hz, 1H), 5.57-5.42 (m, 2H), 4.90 (br s, 1H), 4.78-4.51 (m,1H), 4.23 (s, 3H), 3.55-3.41 (m, 2H), 3.04-2.93 (m, 3H), 2.91-2.82 (m,1H), 2.82-2.75 (m, 4H), 2.23-2.06 (m, 1H), 2.06-1.95 (m, 1H), 1.95-1.77(m, 6H), 1.69 (br s, 1H), 1.42-1.31 (in, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ−76.03 (br s, TFA), −176.02 (dd, J=135.2, 9.3 Hz, F). hLPA1 IC₅₀=50 nM.

Example Structure & Name Analytical & Biology Data Method 261

LCMS; [M +H]⁺ = 464.0; ¹H NMR (500 MHz, CDCl₃) δ 8.18-8.05 (m, 1H),7.82- 7.68 (m, 1H), 5.73-5.46 (m, 2H), 4.96-4.69 (m, 2H), 4.22 (br d, J= 12.9 Hz, 3H), 3.03 (br d, J = 7.2 Hz, 3H), 2.96- 2.84 (m, 1H),2.78-2.63 (m, 3H), 2.21-1.53 (m, 9H), 1.41- 1.22 (m, 4H); ¹⁹F NMR (471MHz, CDCl₃) δ −75.91 (br s, TFA), −175.36 to −181.71 (m, 1F) LPA1 IC₅₀ =145 nM Example 1 (1S,3S)-3-((6-(5-((((2- fluoropropyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 262

LCMS; [M + H]⁺ = 472.2; ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J = 8.8 Hz,1H), 7.94 (br d, J = 9.0 Hz, 1H), 5.57- 5.40 (m, 2H), 4.87 (br s, 1H),4.21 (d, J = 6.4 Hz, 3H), 3.27- 3.06 (m, 2H), 3.04-2.94 (m, 3H), 2.86(br d, J = 3.5 Hz, 1H), 2.76 (d, J = 4.6 Hz, 3H), 2.20-1.56 (m, 8H),1.09- 1.01 (m, 3H), 0.73-0.23 (m, 4H) LPA1 IC₅₀ = 29 nM(1S,3S)-3-((2-methyl-6-(1- methyl-5-(((methyl((2-methylcyclopropyl)methyl)carbamoyl) oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid; mixture ofdiastereomers 263

LCMS; [M + H]⁺ = 474.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J = 8.5Hz, 1H), 7.46 (br d, J = 8.9 Hz, 1H), 5.64 (br s, 2H), 4.77 (br s, 1H),4.09 (s, 3H), 3.18-2.95 (m, 2H), 2.90-2.72 (m, 3H), 2.63 (br d, J = 10.4Hz, 1H), 2.40 (s, 3H), 2.05-1.40 (m 8H), 0.97-0.66 (m, 3H), 0.43- 0.07(m, 4H) LPA1 IC₅₀ = 76 nM (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl((1-methylcyclo- propyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl) pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 264

LCMS; [M + H]⁺ = 474.4; 1H NMR (500 MHz, DMSO-d₆) δ 7.84 (br s, 1H),7.48 (br s, 1H), 5.63 (br d, J = 17.1 Hz, 2H), 4.79 (br s, 1H), 4.11 (s,3H), 3.57 (br dd, J = 12.1, 6.0 Hz, 2H), 3.26 (dd, J = 10.4, 5.8 Hz,1H), 3.20-3.11 (m, 1H), 3.06 (br s, 1H), 2.93 (br s, 1H), 2.90-2.76 (m,3H), 2.63 (br s, 1H), 2.09-1.43 (m, 8H), 0.92-0.64 (m, 9H) LPA1 IC₅₀ =76 nM (1S,3S)-3-((2-methyl-6-(1- methyl-5-(((methyl(neopentyl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

Example 265 (1 S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

265A. 3,6-dibromo-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine

A solution of ethyl 3,6-dibromopicolinate (3.0 g, 9.71 mmol) in THF (50mL) was stirred at 0° C., then LiBH₄ (7.28 mL of a 2M solution in THF,14.57 mmol) was added portionwise over 5-10 min. Vigorous gas evolutionensued. The reaction mixture was stirred at rt overnight, then wasquenched with 1N aq. HCl slowly, adjusting the pH to ˜7. The mixture waspartitioned between EtOAc and water (50 mL each) and extracted withEtOAc (3×). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (24 g SiO₂) toprovide 3,6-dibromopyridin-2-yl)methanol (1.89 g, 7.08 mmol, 72.9%yield).

To a solution of (3,6-dibromopyridin-2-yl)methanol (2.46 g, 9.22 mmol)in CH₂Cl₂ (12 mL) was added 3,4-dihydro-2H-pyran (2.52 mL, 27.6 mmol)and pyridinium p-toluenesulfonate (0.116 g, 0.461 mmol). The reactionwas stirred overnight at rt, then quenched with water and extracted withDCM, washed with water, brine, dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (24 g SiO₂, continuous gradient from0-100% EtOAc/hexanes over 20 min) to give the title compound (3.4 g,9.40 mmol, 100% yield). 1H NMR (500 MHz, CDCl₃) δ 7.72 (d, J=8.53 Hz,1H), 7.32 (d, J=8.25 Hz, 1H), 4.94 (d, J=11.83 Hz, 1H), 4.88 (t, J=3.30Hz, 1H), 4.69 (d, J=11.83 Hz, 1H), 3.94-4.09 (m, 1H), 3.49-3.70 (m, 1H),1.49-2.00 (m, 8H)

265B.3-(5-Bromo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)prop-2-yn-1-ol

To a solution of Example 265A (3.4 g, 9.69 mmol) and prop-2-yn-1-ol(0.677 mL, 11.62 mmol) in MeCN (30 mL) was added Et₃N (6.00 mL). Thesolution was degassed with N₂ for 5 mins, after which Pd(Ph₃)₂Cl₂ (0.340g, 0.484 mmol) and CuI (0.092 g, 0.484 mmol) were added. The reactionmixture was degassed with N₂ for 5 min, then was stirred at rt for 16 hunder N₂. LCMS indicated at this time indicated that the reaction wascomplete. The reaction mixture was filtered through a pad of Celite andwashed with EtOAc (4×30 mL). The filtrate was concentrated in vacuo andthe residue was chromatographed (80 g SiO₂, elution by continuousgradient from 0% to 100% EtOAc/Hex over 80 min at 35 mL/min) to give thetitle compound (2.90 g, 8.89 mmol, 92% yield). ¹H NMR (500 MHz, CDCl₃) δ7.86 (d, J=8.25 Hz, 1H), 7.26 (d, J=8.25 Hz, 1H), 4.98 (d, J=11.55 Hz,1H), 4.88 (t, J=3.30 Hz, 1H), 4.69 (d, J=11.55 Hz, 1H), 4.53 (d, J=6.05Hz, 2H), 3.99 (dt, J=2.75, 10.45 Hz, 1H), 3.53-3.65 (m, 1H), 1.47-1.95(m, 6H)

265C.(4-(5-Bromo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)methanol

To a solution of Example 265B (2.9 g, 8.89 mmol) in dioxane (40 mL) wasadded CuI (0.068 g, 0.356 mmol),chloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)Ruthenium(II)(0.283 g, 0.356 mmol). The resulting suspension was degassed with N₂ for3 min, after which trimethylsilylmethyl azide (1.404 g, 9.78 mmol) wasadded. The mixture was degassed with N₂ for another 5 min, then washeated in an oil bath at 50° C. for 20 h under N₂, then was cooled tort. The mixture was filtered through Celite; the filtrate wasconcentrated in vacuo, and chromatographed (120 g SiO₂; elution withcontinuous gradient from 0 to 60% EtOAc/Hex over 65 min at 120 mL/min)to give the title compound (2.30 g, 5.05 mmol, 56.8% yield). ¹H NMR (500MHz, CDCl₃) δ 8.10 (d, J=8.25 Hz, 1H), 7.97 (d, J=8.53 Hz, 1H), 6.41 (t,J=7.57 Hz, 1H), 5.05 (d, J=14.30 Hz, 1H), 4.86 (t, J=3.30 Hz, 1H), 4.80(dd, J=1.38, 7.43 Hz, 2H), 4.76 (d, J=14.03 Hz, 1H), 3.86-3.97 (m, 1H),3.83 (s, 2H), 3.53-3.64 (m, 1H), 1.51-2.02 (m, 8H), 0.18-0.27 (m, 9H)

265D.(4-(5-Bromo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate

TBAF (5.56 mL of a 1M solution in THF, 5.56 mmol) was added dropwise toa solution of Example 265C (2.3 g, 5.05 mmol) in THF (15 mL) and thereaction mixture was stirred at rt overnight, then was quenched withsatd aq. NaHCO₃ (50 mL) and stirred for 20 min at rt. The mixture wasextracted with EtOAc (2×100 mL); the combined organic extracts weredried with Na₂SO₄, filtered and concentrated in vacuo. The crude productwas chromatographed (40 g SiO₂; continuous gradient from 0% to 100%EtOAc over 30 min, at 20 mL/min) to give(4-(5-bromo-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol(1.69 g, 4.41 mmol, 87% yield). To a solution of this material (0.41 g,1.07 mmol) and pyridine (0.433 mL, 5.35 mmol) in DCM (5 mL) was added4-nitrophenyl chloroformate (0.431 g, 2.140 mmol) in DCM (2 mL). Thereaction mixture was stirred at rt overnight, then(cyclobutylmethyl)methylamine (0.318 g, 3.21 mmol) was added, followedby Et₃N (1.49 mL, 10.7 mmol). The reaction was stirred at rt for 3 h,then was partitioned between DCM and sat'd aq. NaHCO₃. The organic layerwas washed with brine and concentrated in vacuo. The residue waschromatographed (40 g SiO₂; continuous gradient from 0% to 100% EtOAcover 30 min, at 20 ml/min) to give the title compound (0.52 g, 0.921mmol, 86% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.05 (d, J=8.3 Hz, 1H), 7.96(d, J=8.3 Hz, 1H), 5.83 (br d, J=16.0 Hz, 2H), 5.01 (d, J=11.8 Hz, 1H),4.93 (t, J=3.2 Hz, 1H), 4.77 (d, J=12.1 Hz, 1H), 4.10-4.24 (m, 3H),3.90-4.07 (m, 1H), 3.53-3.70 (m, 1H), 3.10-3.42 (m, 2H), 2.70-2.98 (m,3H), 1.46-2.05 (m, 13H)

265E.(4-(5-hydroxy-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl(cyclobutylmethyl)(methyl)carbamate

To a degassed solution of Example 265D (510 mg, 1.00 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (509 mg,2.01 mmol) and KOAc (295 mg, 3.01 mmol) in THF (4013 μl) was addedPdCl₂(dppf) (36.7 mg, 0.050 mmol). The vial was purged with N₂, sealedand stirred at 80° C. overnight, then was cooled to rt. The mixture wasdiluted with EtOAc and filtered; the filtrate was concentrated in vacuo,re-dissolved in THF (5 mL) and this crude pinacol boronate product wasused in the next step without further purification. To the solution ofthis crude pinacol boronate product in THF (5 mL) was added aq. NaOH(2.01 mL of a 1 M solution, 2.01 mmol), followed by aq. H₂O₂ (0.830 mL,10.03 mmol). The reaction mixture was stirred at rt for 2 h, after whichsatd. aq. Na₂S₂O₃ (1 mL) was added; the mixture was stirred at rt for 10min, then was extracted with EtOAc (3×10 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (24 g SiO₂; continuous gradient from 0 to 100% EtOAc/Hexover 20 min at 20 mL/min) to give the title compound (379 mg, 0.851mmol, 85% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.22 (br s, 1H), 8.07 (d,J=8.53 Hz, 1H), 7.30 (d, J=8.53 Hz, 1H), 5.73 (br d, J=9.08 Hz, 2H),5.14 (d, J=12.93 Hz, 1H), 4.92 (d, J=12.65 Hz, 1H), 4.77-4.86 (m, 1H),4.15 (br d, J=5.23 Hz, 3H), 3.96-4.06 (m, 1H), 3.60-3.73 (m, 1H), 3.34(br d, J=7.43 Hz, 1H), 3.18 (br d, J=6.88 Hz, 1H), 2.74-2.99 (m, 3H),1.60-1.98 (m, 13H)

265E. Isopropyl(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(hydroxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of Example 265D (275 mg, 0.617 mmol), Example 1F (610 mg,1.54 mmol) in t-AmOH (5 mL) was added Cs₂CO₃ (603 mg, 1.85 mmol); thereaction was stirred at 65° C. for 24 h. Then more Example 1F (244 mg,0.617 mmol) and Cs₂CO₃ (241 mg, 0.741 mmol) were added to the reaction,which was heated at 65° C. for another 24 h, then cooled to rt. Water (5mL) was added and the mixture was stirred at rt for 10 min, then wasextracted with EtOAc (3×10 mL). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo. The residue was chromatographed (24g SiO₂, continuous gradient from 0 to 100% EtOAc/Hex over 18 min at 15mL/min) to give (1S,3S)-isopropyl 3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy)cyclohexanecarboxylate(290 mg, 0.402 mmol, 65.1% yield).

A mixture of this THP ether (330 mg, 0.468 mmol) and PPTS (23.5 mg,0.094 mmol) in MeOH (4 mL) was heated at 60° C. overnight, then wascooled to rt. Volatiles were removed in vacuo and the residue waspartitioned between DCM and satd aq. NaHCO₃. The organic extract wasdried (Na₂SO₄) was concentrated in vacuo. The crude product waschromatographed (24 g SiO₂; continuous gradient from 0 to 100% EtOAc/Hexover 20 min at 20 mL/min and then at 100% EtOAc for 10 min) to give thetitle compound (274 mg, 0.491 mmol, 100% yield). ¹H NMR (500 MHz, CDCl₃)δ 8.13 (br dd, J=3.71, 8.12 Hz, 1H), 7.32 (d, J=8.53 Hz, 1H), 5.70 (s,2H), 4.99-5.14 (m, 1H), 4.78-4.90 (m, 1H), 4.75 (br s, 1H), 4.24 (s,3H), 3.20-3.34 (m, 2H), 2.82-2.96 (m, 3H), 2.67-2.79 (m, 1H), 2.33-2.63(m, 1H), 1.46-2.15 (m, 16H), 1.07-1.32 (m, 6H)

Example 265

To a solution of 265E (17 mg, 0.032 mmol) in THF (0.5 mL) was added 4drops of MeOH at rt, after which LiOH·H₂O (0.080 mL, 0.321 mmol) wasadded. The reaction mixture was stirred at rt overnight, then waspurified by preparative HPLC ((PHENOMENEX®, Axia 5p C18 30×100 mmcolumn; detection at 220 nm; flow rate=40 mL/min; continuous gradientfrom 0% B to 100% B over 10 min+2 min hold time at 100% B, whereA=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA)) to give thetitle compound (15 mg, 0.024 mmol, 75% yield). ¹H NMR (500 MHz, CDCl₃) δ8.19 (br d, J=8.25 Hz, 1H), 7.65 (br d, J=8.53 Hz, 1H), 5.51-5.66 (m,2H), 4.90-5.12 (m, 2H), 4.84 (br s, 1H), 4.24 (s, 3H), 3.29 (br dd,J=7.15, 16.78 Hz, 2H), 2.88 (br s, 4H), 2.38-2.68 (m, 1H), 1.49-2.22 (m,15H). LCMS, [M+H]⁺=488.3. hLPA1 IC₅₀=68 nM

Example 266(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(fluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

To a solution of Example 265E (50 mg, 0.094 mmol) in DCM (1 mL) at 0°C., was added bis(2-methoxyethyl)aminosulfur trifluoride (0.061 mL,0.283 mmol) dropwise under N₂. The reaction mixture was gradually warmedto rt and stirred at rt for 2 h, then was slowly quenched by addition ofsatd aq. NaHCO₃ followed by DCM. The organic layer was dried using astream of N2 and the crude product (1S,3S)-isopropyl3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(fluoromethyl)pyridin-3-yl)oxy)cyclohexanecarboxylate) was used in the next step without furtherpurification. To a solution of the crude isopropyl ester (50 mg, 0.094mmol) in THF (0.5 mL) was added 4 drops of MeOH at rt, followed by aq.LiOH (0.235 mL, 0.941 mmol). The reaction mixture was stirred at rtovernight, then was filtered. The crude product was purified bypreparative HPLC (PHENOMENEX®, Axia 5 μC18 30×100 mm column; detectionat 220 nm; flow rate=40 mL/min; continuous gradient from 0% B to 100% Bover 10 min+2 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA to give the title compound (25 mg, 0.039mmol, 41.8% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.19 (br d, J=8.53 Hz,1H), 7.62-7.71 (m, 1H), 5.49-5.77 (m, 4H), 4.84 (br s, 1H), 4.22 (br d,J=4.40 Hz, 3H), 3.16-3.44 (m, 2H), 2.80-2.98 (m, 4H), 1.26-2.68 (m,16H). LCMS, [M+H]+=490.3. hLPA1 IC₅₀=27 nM.

Example 267(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

To a mixture of Example 265E (80 mg, 0.151 mmol) and 75 mg of Celite inDCM (1.5 mL) was added pyridinium dichromate (73.9 mg, 0.196 mmol). Thereaction mixture was stirred at rt for 90 min, after which morepyridinium dichromate (73.9 mg; 0.196 mmol) was added, and the reactionwas stirred overnight at rt. EtOAc was added and the mixture wasfiltered through Celite. The filtrate was concentrated in vacuo, and thecrude product was chromatographed (4 g SiO₂, continuous gradient from 0to 100% EtOAc/Hex over 12 min at 8 mL/min) to give (1S,3S)-isopropyl3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-formylpyridin-3-yl)oxy)cyclohexanecarboxylate(15 mg, 0.028 mmol, 18% yield). To a RT solution of the above aldehyde(15 mg, 0.028 mmol) in DCM (0.3 mL) was addedbis(2-methoxyethyl)aminosulfur trifluoride (0.032 mL, 0.148 mmol) in oneportion. The mixture was stirred at rt for 2 h; volatiles were removedvia an N₂ stream, and the crude difluoromethyl product (1S,3S)-isopropyl3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexanecarboxylate was directly in the next step without furtherpurification. To a solution of this isopropyl ester (13 mg, 0.024 mmol)in THF (0.5 mL) was added aq. LiOH (0.118 mL, 0.473 mmol) and 4 drops ofMeOH. The reaction mixture was stirred at rt for 2 days, filtered andthe crude product was purified by preparative HPLC, (PHENOMENEX®, Axia 5μC18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 0% B to 100% B over 10 min+2 min hold time at100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) togive the title compound (2 mg, 3.19 μmol, 13.5% yield). ¹H NMR (400 MHz,CDCl₃) δ 8.28 (d, J=8.80 Hz, 1H), 7.37-7.65 (m, 1H), 6.62-7.05 (m, 1H),5.71 (br s, 2H), 4.80 (br d, J=2.64 Hz, 1H), 4.17 (br d, J=7.92 Hz, 3H),3.09-3.45 (m, 2H), 2.72-3.02 (m, 4H), 1.36-2.65 (m, 15H). LCMS,[M+H]⁺=508.2. hLPA IC₅₀=30 nM

Alternatively, the title compound can also be synthesized as follows.

267A. (3,6-Dibromopyridin-2-yl)methanol

To a 0° C. solution of ethyl 3,6-dibromopicolinate (5.0 g, 16.2 mmol) inTHF (30 mL) was added LiBH₄ in THF (12.14 mL of a 2 M solution, 24.28mmol) portionwise over 10 min. Vigorous gas evolution ensued. After 1 hat rt, the reaction mixture was slowly quenched with satd aq., stirredfor 10 min, then was extracted with EtOAc. The pH of the aqueous phasewas adjusted to 7-8 by addition of 1N aq. HCl, then was extracted againwith EtOAc. The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The crude material was chromatographed (40 gSiO₂; EtOAc/Hexane; continuous gradient from 0% to 100% EtOAc over 30min, at 20 mL/min) to give the title compound (3.0 g, 11.24 mmol, 69.4%yield), 1H NMR (500 MHz, CDCl₃) δ 7.72 (d, J=7.98 Hz, 1H), 7.35 (d,J=7.98 Hz, 1H), 4.77 (d, J=4.95 Hz, 2H), 3.78 (t, J=5.09 Hz, 1H)

267B. 3,6-Dibromo-2-(difluoromethyl)pyridine

Anhydrous DMSO (4.04 mL, 56.9 mmol) was added dropwise to a solution of(COCl)₂ (2.277 mL, 26.0 mmol) in DCM (25 mL) at −78° C. After stirringat −78° C. for 15 min, a solution of Example 267A (2.17 g, 8.13 mmol) inDCM (25 mL) was added dropwise. After stirring for 15 min at −78° C.,TEA (10.2 mL, 73.2 mmol) was added dropwise. The reaction was allowed towarm to rt over 1 h (the reaction mixture became cloudy); more DCM (50mL) was added and the mixture was stirred for 2 h at rt. The reactionwas quenched with brine (20 mL) and extracted with DCM (2×50 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuo.The crude oil was chromatographed (80 g SiO₂; elution with EtOAc/Hexane(continuous gradient from 0% to 60% over 20 min) to give3,6-dibromopicolinaldehyde (1.92 g, 7.25 mmol, 89% yield) as a lightyellowish oil. To a solution of the 3,6-dibromopicolin-aldehyde (1.5 g,5.66 mmol) in DCM (6 mL) at rt was added bis(2-methoxyethyl)aminosulfurtrifluoride (1.46 mL, 6.79 mmol) in one portion. The mixture was stirredat rt for 1 h, then was carefully quenched with sat'd aq. NaHCO₃,adjusted to pH=7-8 and extracted with DCM (2λ). The combined organicextracts were concentrated in vacuo. The residue was chromatographed(EtOAc/Hexane; continuous gradient from 0% to 100% EtOAc over 20 min, at15 mL/min) to give the title compound (1.48 g, 5.16 mmol, 91% yield). ¹HNMR (500 MHz, CDCl₃) δ 7.83 (d, J=8.53 Hz, 1H), 7.51 (d, J=8.53 Hz, 1H),6.65-7.00 (m, 1H)

Example 267B can then be used as the starting material for the synthesisof Example 267. The synthetic sequence is analogous to that used for thesynthesis of Example 1 (i.e. regioselective Sonogashira coupling of theless hindered bromide of Example 267B with propargyl alcohol, followedby Ru-mediated [3+2] cycloaddition with trimethylsilyl azide to form the1,2,3-triazole, etc.).

Example 267: 1H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=8.80 Hz, 1H),7.37-7.65 (m, 1H), 6.62-7.05 (m, 1H), 5.71 (br s, 2H), 4.80 (br d,J=2.64 Hz, 1H), 4.17 (br d, J=7.92 Hz, 3H), 3.09-3.45 (m, 2H), 2.72-3.02(m, 4H), 1.36-2.65 (m, 15H). LCMS, [M+H]⁺=508.2 hLPA1 IC₅₀=30 nM

Example 268(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

268A. 3,6-Dibromo-2-(methoxymethyl)pyridine

A solution of (3,6-dibromopyridin-2-yl)methanol (1.67 g, 6.26 mmol) inanhydrous THF (29 mL) was slowly added to a stirring suspension of NaH(0.30 g, 7.51 mmol) in anhydrous THF (5 ml) at 0-5° C. under N₂. Aftergas evolution stopped, Mel (0.587 mL, 9.38 mmol) was added slowlydropwise and the reaction was warmed to rt over 1 h. Brine (10 mL) wasadded slowly to the reaction, which was then extracted with EtOAc (2×50mL). The combined organic extracts were dried (Na₂SO₄) and concentratedin vacuo. The crude material was chromatographed (24 g SiO₂;EtOAc/Hexane; continuous gradient from 0% to 100% EtOAc over 30 min, at10 mL/min) to give the title compound (1.70 g, 6.05 mmol, 97% yield). ¹HNMR (500 MHz, CDCl₃) δ 7.72 (d, J=8.25 Hz, 1H), 7.34 (d, J=8.25 Hz, 1H),4.66 (s, 2H), 3.52 (s, 3H).

Example 268B was then used for the synthesis of Example 268. Thesynthetic sequence is analogous to that used for the synthesis ofExample 1 (i.e. regioselective Sonogashira coupling of the less hinderedbromide of Example 268B with propargyl alcohol, followed by Ru-mediated[3+2] cycloaddition with trimethylsilyl azide to form the1,2,3-triazole, etc.).

Example 268: ¹H NMR (500 MHz, DMSO-d6) δ 7.95 (br d, J=8.24 Hz, 1H),7.60 (br d, J=8.85 Hz, 1H), 5.63 (br d, J=12.82 Hz, 2H), 4.81 (br s,1H), 4.53 (br s, 2H), 4.10 (br s, 3H), 3.03-3.27 (m, 2H), 2.68-2.82 (m,3H), 2.59 (br d, J=10.38 Hz, 1H), 2.56 (s, 3H), 1.32-2.36 (m, 16H);LCMS, [M+H]⁺=502.3; hLPA1 IC₅₀=103 nM

Example 269(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

Example 269 was synthesized using commercially available3,6-dibromo-2-(trifluoromethyl) pyridine, using the same syntheticsequence as for the preparation of Example 1.

Example 269: ¹H NMR (500 MHz, CDCl₃) δ 8.39 (br d, J=8.80 Hz, 1H), 7.54(d, J=9.08 Hz, 1H), 5.71 (br s, 1H), 4.86 (br s, 1H), 4.21 (br d,J=13.76 Hz, 3H), 3.12-3.40 (m, 2H), 2.89-2.99 (m, 1H), 2.74-2.89 (m,3H), 2.35-2.66 (m, 1H), 2.17-2.37 (m, 1H), 1.42-2.29 (m, 14H)

LCMS, [M+H]⁺=526.2; hLPA₁ IC₅₀=10 nM.

Example 270(1S,3S)-3-((2-cyano-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

270A. 3,6-Dibromopicolinonitrile

To a suspension of 3,6-dibromopicolinic acid (0.5 g, 1.780 mmol), NH₄Cl(0.381 g, 7.12 mmol) and Et₃N (1.985 ml, 14.24 mmol) in THF (7.12 mL)was added 1-propanephosphonic anhydride (4.24 mL, 7.12 mmol) dropwise at0° C. The reaction was slowly warmed to rt, then was heated to 80° C.for 48 h, then was cooled to rt. The mixture was partitioned betweenwater and EtOAc (10 mL each) and extracted with EA (2×10 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuo.The residue was chromatographed (40 g SiO₂; EtOAc/Hexane; continuousgradient from 0% to 100% EtOAc over 30 min, at 20 mL/min) to give thetitle compound (0.32 g, 1.22 mmol, 68.6% yield) as a white solid. ¹H NMR(500 MHz, CDCl₃) δ 7.88 (d, J=8.53 Hz, 1H), 7.60 (d, J=8.53 Hz, 1H).

Example 270 was synthesized using Example 270A, using the same syntheticsequence as for the preparation of Example 1 (except that N-methyl,N-propylamine was used to generate the carbamate of Example 270 ratherthan the N-methyl, N-cyclobutylmethylamine that was used in Example 1).

Example 270: ¹H NMR (500 MHz, DMSO-d₆) δ 8.30 (d, J=9.16 Hz, 1H), 7.98(d, J=9.16 Hz, 1H), 5.54 (br d, J=19.53 Hz, 2H), 5.01 (br s, 1H), 4.14(s, 3H), 3.00-3.25 (m, 2H), 2.77 (br d, J=9.16 Hz, 3H), 2.63 (br t,J=10.22 Hz, 1H), 1.15-2.21 (m, 10H), 0.58-0.96 (m, 3H)

LCMS, [M+H]⁺=457.1; hLPA1 IC₅₀=11 nM

Example 271(1S,3S)-3-((6-(5-((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(2-hydroxypropan-2-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

271A. Ethyl3-bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)picolinate

This compound was synthesized from commercially available ethyl3,6-dibromopicolinate, using the same synthetic sequence as for Example265. ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J=8.53 Hz, 1H), 8.05 (d, J=8.53Hz, 1H), 5.26-5.40 (m, 2H), 4.76 (t, J=3.44 Hz, 1H), 4.50 (q, J=7.15 Hz,2H), 4.19 (s, 3H), 3.83 (ddd, J=3.03, 8.05, 11.21 Hz, 1H), 3.46-3.62 (m,1H), 1.51-1.88 (m, 6H), 1.48 (t, J=7.15 Hz, 3H)

271B. Ethyl3-hydroxy-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)picolinate

To a degassed solution of Example 271A (433 mg, 1.02 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (517 mg,2.036 mmol) and KOAc (300 mg, 3.05 mmol) in THF (4.07 mL) was addedPdCl₂(dppf) (37.2 mg, 0.051 mmol). The vial was purged with N₂, sealedand stirred at 80° C. overnight, then was cooled to rt. The mixture wasfiltered and the filtrate (crude pinacol boronate) was used directly inthe next step without further purification

To a solution of the above crude boronate product (397 mg, 1.018 mmol)in EtOAc (7 mL) and THF (2 mL) was added H₂O₂ (0.946 mL, 10.2 mmol). Thereaction was stirred at rt for 3 h, then was extracted with EtOAc. Tothe aqueous phase was added satd aq. Na₂S₂O₃ (3 mL) and 2 drops of 1Naq. NaOH; the mixture was stirred for 5 min and extracted again withEtOAc (2×5 mL). The combined organic extracts were concentrated invacuo. The residue was chromatographed (40 g SiO₂;EtOAc/Hexane-continuous gradient from 0% to 100% EtOAc over 30 min, at20 mL/min) to give the title compound (328 mg, 88% yield). ¹H NMR (500MHz, CDCl₃) δ 10.74 (s, 1H), 8.35 (d, J=8.80 Hz, 1H), 7.46 (d, J=8.80Hz, 1H), 5.22-5.57 (m, 2H), 4.81 (t, J=3.58 Hz, 1H), 4.52 (dq, J=2.06,7.11 Hz, 2H), 4.19 (s, 3H), 3.93 (br s, 1H), 3.84 (ddd, J=2.61, 8.32,11.07 Hz, 1H), 3.43-3.60 (m, 1H), 1.48-2.06 (m, 9H)

271C.2-(2-hydroxypropan-2-yl)-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol

To a solution of Example 271B (0.3 g, 0.828 mmol) in THF (7 mL) wasadded dropwise CH₃MgBr (1.95 mL of a 3.5 M solution in THF, 6.62 mmol)at 0° C. The resulted mixture was allowed to warm to rt and stirred atrt for 3 h. Satd aq. NH₄Cl was then carefully added to quench thereaction, which was extracted with EtOAc. The aqueous layer wascarefully adjusted to pH 6 by using 1 N aq. HCl, then extracted againwith EtOAc (2λ). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The crude product was chromatographed (24 g SiO₂;EtOAc/Hexane-continuous gradient from 0% to 100% EtOAc over 30 min, at10 mL/min) to give the title compound (110 mg, 0.316 mmol, 38.1% yield).

Example 271

Example 271C was converted to Example 271 by a similar sequence used toconvert Example 1C to Example 1.

¹H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J=8.54 Hz, 1H), 7.59 (br d, J=8.54Hz, 1H), 5.49 (s, 2H), 4.85 (br s, 1H), 4.13 (br s, 2H), 3.79 (br d,J=16.78 Hz, 1H), 3.07-3.26 (m, 2H), 2.88 (s, 1H), 2.68-2.75 (m, 2H),2.55 (s, 3H), 1.19-2.16 (m, 20H). LCMS, [M+H]⁺=516.3. hLPA₁ IC₅₀=225 nM

Example 272(1S,3S)-3-((2-Methoxy-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

Example 272 was synthesized from 3,6-dibromo-2-(methoxy)pyridine usingthe same synthetic sequence as for the preparation of Example 1 from3,6-dibromopyridine. LCMS, [M+H]₊=462.1; ¹H NMR (500 MHz, CDCl₃) δ 7.81(d, J=8.0 Hz, 1H), 7.33-7.30 (m, 1H), 5.79 (br s, 2H), 4.72-4.67 (m,1H), 4.18 (s, 3H), 4.04 (s, 3H), 3.25 (br t, J=7.3 Hz, 1H), 3.18-3.07(m, 1H), 3.06-2.95 (m, 1H), 2.92 (s, 1.5H), 2.83 (s, 1.5H), 2.16-2.07(m, 2H), 2.05-1.83 (m, 4H), 1.79-1.68 (m, 2H), 1.68-1.52 (m, 2H),1.50-1.33 (m, 1H), 0.95-0.85 (m, 1.5H), 0.76 (br t, J=7.2 Hz, 1.5H)hLPA₁ IC₅₀=4 nM

The following examples were synthesized according to the proceduresdescribed above.

Example Structure & Name Analytical & Biology Data Method 273

LCMS, [M + H]+ = 512.4 1H NMR (500 MHz, DMSO- d₆) 6 8.33 (br d, J = 8.85Hz, 1H), 7.87-8.11 (m, 1H), 5.62 (br d, J = 17.09 Hz, 2H), 5.06 (br s,1H), 4.18 (s, 2H), 2.69- 3.38 (m, 6H), 2.11 (br d, J = 13.43 Hz, 1H),1.78-2.02 (m, 3H), 1.44-1.76 (m, 3H), 1.14-1.35 (m, 1H), 1.05 (d, J =6.10 Hz, 1H), 0.71-0.97 (m, 1H), 0.47 (br s, 1H), 0.30 (br s, 2H),0.13-0.26 (m, 1H) hLPA1 IC₅₀ = 7 nM. Example 269 (1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl) carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- (trifluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 274

1H NMR (500 MHz, DMSO- d6) δ 8.27 (br d, J = 8.54 Hz, 1H), 7.95 (br d, J= 8.85 Hz, 1H), 5.57 (br d, J = 13.43 Hz, 2H), 5.01 (br s, 1H), 4.13 (s,2H), 2.97-3.21 (m, 2H), 2.93 (q, J = 7.22 Hz, 2H), 2.65-2.79 (m, 3H),1.21-2.13 (m, 8H), 1.17 (t, J = 7.17 Hz, 3H), 0.50- 0.85 (m, 2H) LCMS,[M + H]+ = 499.9 hLPA1 IC₅₀ = 28 nM. Example 269(1S,3S)-3-((6-(1-methyl-5- (((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-2- (trifluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 275

1H NMR (500 MHz, DMSO- d6) δ 8.27 (br d, J = 8.85 Hz, 1H), 7.94 (br d, J= 8.85 Hz, 1H), 5.55 (br d, J = 12.82 Hz, 2H), 5.00 (br s, 1H), 4.13 (brs, 3H), 2.99-3.23 (m, 2H), 2.92 (q, J = 7.32 Hz, 1H), 2.74 (br s, 1H),2.70 (br s, 2H), 1.33-2.13 (m, 10H), 1.08-1.27 (m, 3H), 0.91-1.00 (m,1H), 0.85 (br s, 1H), 0.61 (br s, 2H) LCMS, [M + H]+ = 514.1 hLPA1 IC₅₀= 5.6 nM. Example 269 (1S,3S)-3-((6-(5- (((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-(trifluoromethyl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 276

1H NMR (500 MHz, DMSO- d6) δ 8.27 (d, J = 8.84 Hz, 1H), 7.96 (d, J =9.00 Hz, 1H), 5.56 (br s, 2H), 5.01 (br s, 1H), 4.13 (s, 3H), 3.65 (m,1H), 2.54-2.70 (m, 4H), 1.73-2.14 (m, 4H), 1.25-1.71 (m, 12H) LCMS, [M +H]+ = 526.5 hLPA1 IC₅₀ = 15 nM. Example 269 (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(trifluoro methyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 277

1H NMR (500 MHz, DMSO- d6) δ 8.16 (br d, J = 8.24 Hz, 1H), 7.82 (br d, J= 8.85 Hz, 1H), 7.01-7.34 (m, 1H), 5.62 (br d, J = 13.12 Hz, 2H), 4.94(br s, 1H), 4.13 (s, 3H), 2.95- 3.22 (m, 2H), 2.75 (br d, J = 16.78 Hz,3H), 2.66 (br t, J = 10.68 Hz, 1H), 2.06 (br d, J = 13.43 Hz, 1H),1.39-1.95 (m, 8H), 1.18-1.34 (m, 2H), 0.52-0.88 (m, 3H) LCMS, [M + H]+ =482.2 hLPA1 IC₅₀ = 35 nM Example 267 (1S,3S)-3-((2-(difluoromethyl)-6-(1-methyl-5- (((methyl(propyl)carbamoyl)oxy) methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane- 1-carboxylic acid 278

1H NMR (500 MHz, DMSO- d6) δ 8.16 (d, J = 8.85 Hz, 1H), 7.82 (br d, J =8.85 Hz, 1H), 6.87-7.22 (m, 1H), 5.62 (br d, J = 10.99 Hz, 2H), 4.93 (brs, 1H), 4.13 (br s, 3H), 2.96- 3.29 (m, 2H), 2.61-2.87 (m, 4H),0.52-2.18 (m, 15H) LCMS, [M + H]⁺ = 496.2 hLPA1 IC₅₀ = 22 nM Example 267(1S,3S)-3-((6-(5- (((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 279

1H NMR (500 MHz, DMSO- d6) δ 8.16 (d, J = 8.75 Hz, 1H), 7.80 (d, J =8.92 Hz, 1H), 6.84- 7.23 (m, 1H), 5.63 (s, 2H), 4.92 (br s, 1H), 4.13(s, 3H), 2.83 (s, 2H), 2.61-2.74 (m, 1H), 2.55 (s, 3H), 2.01-2.17 (m,1H), 1.40-1.95 (m, 7H), 1.25 (s, 1H), −0.16-0.98 (m, 5H) LCMS, [M + H]+= 494.2 hLPA1 IC₅₀ = 21 nM Example 267 (1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl) carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- (difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 280

1H NMR (500 MHz, DMSO- d6) δ 8.16 (d, J = 8.75 Hz, 1H), 7.80 (d, J =8.92 Hz, 1H), 6.89- 7.22 (m, 1H), 5.62 (s, 2H), 4.92 (br s, 1H), 2.74(s, 3H), 2.60-2.72 (m, 1H), 2.55 (s, 3H), 1.79 (d, J = 123.19 Hz, 15H)LCMS, [M + H]+ = 494.2 hLPA1 IC₅₀ = 22 nM Example 267 (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(difluoromethyl) pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 281

1H NMR (500 MHz, DMSO- d6) δ 8.16 (d, J = 8.85 Hz, 1H), 7.82 (br d, J =8.85 Hz, 1H), 6.88-7.19 (m, 1H), 5.62 (br d, J = 10.99 Hz, 2H), 4.93 (brs, 1H), 4.02-4.24 (m, 3H), 2.97- 3.34 (m, 2H), 2.60-2.85 (m, 4H),−0.24-2.48 (m, 16H) LCMS, [M + H]+ = 508.2 hLPA1 IC₅₀ = 35 nM Example267 (1S,3S)-3-((6-(5- (((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-(difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 282

1H NMR (500 MHz, DMSO- d6) δ 8.16 (br d, J = 8.75 Hz, 1H), 7.80 (br d, J= 8.84 Hz, 1H), 6.85-7.47 (m, 6H), 5.69 (br s, 2H), 4.91 (br s, 1H),4.37 (br s, 2H), 4.07 (br d, J = 14.22 Hz, 3H), 2.61-2.89 (m, 4H),1.42-2.16 (m, 8H) LCMS, [M + H]+ = 530.9 hLPA1 IC₅₀ = 19 nM Example 267(1S,3S)-3-((6-(5- (((benzyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2- (difluoromethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 283

1H NMR (500 MHz, DMSO- d6) δ 7.97 (br d, J = 7.02 Hz, 1H), 7.61 (br d, J= 8.54 Hz, 1H), 5.66 (br d, J = 8.54 Hz, 2H), 4.84 (br s, 2H), 4.54 (brd, J = 2.75 Hz, 2H), 4.11 (s, 3H), 3.34 (s, 1H), 2.97-3.22 (m, 2H),2.71-2.86 (m, 3H), 2.62-2.70 (m, 1H), 1.23-2.13 (m, 10H), 1.01 (d, J =6.41 Hz, 1H), 0.56-0.87 (m, 3H) LCMS, [M + H]+ = 476.2 hLPA1 IC₅₀ = 475nM Example 268 (1S,3S)-3-((2-(methoxymethyl)-6-(1-methyl-5-(((methyl(propyl) carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyrdin-3-yl)oxy) cyclohexane-1-carboxylic acid 284

1H NMR (500 MHz, DMSO- d6) δ 7.98 (br d, J = 8.85 Hz, 1H), 7.61 (br d, J= 8.85 Hz, 1H), 5.66 (br d, J = 8.85 Hz, 2H), 4.84 (br s, 1H), 4.54 (d,J = 2.44 Hz, 2H), 4.11 (s, 3H), 3.00-3.28 (m, 2H), 2.61-2.85 (m, 4H),0.57-2.16 (m, 18H) LCMS, [M + H]+ = 490.3 hLPA1 IC₅₀ = 48 nM Example 268(1S,3S)-3-((6-(5-(((butyl(methyl) carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2- (methoxymethyl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 285

1H NMR (500 MHz, DMSO- d6) δ 7.98 (br d, J = 8.54 Hz, 1H), 7.60 (br d, J= 8.54 Hz, 1H), 5.66 (br d, J = 12.82 Hz, 2H), 4.82 (br s, 1H), 4.42-4.65 (m, 2H), 4.12 (s, 3H), 2.92-3.22 (m, 2H), 2.61-2.89 (m, 4H),0.64-2.16 (m, 14H), −0.11-0.53 (m, 4H) LCMS, [M + H]+ = 488.3 hLPA1 IC₅₀= 1008 nM Example 268 (1S,3S)-3-((6-(5-((((cyclopropylmethyl)(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl)pyridin- 3-yl)oxy)cyclohexane-1- carboxylic acid286

1H NMR (500 MHz, DMSO- d6) δ 7.96 (br d, J = 8.54 Hz, 1H), 7.60 (br d, J= 8.85 Hz, 1H), 5.63 (s, 2H), 4.82 (br s, 1H), 4.52 (br s, 2H), 4.09 (s,3H), 3.32 (s, 3H), 2.59-2.81 (m, 4H), 1.26-2.24 (m, 15H) LCMS, [M + H]+= 488.3 hLPA1 IC₅₀ = 92 nM Example 268 (1S,3S)-3-((6-(5-(((cyclobutyl(methyl)carbamoyl)oxy)methyl)- 1-methyl-1H-1,2,3-triazol-4-yl)-2-(methoxymethyl) pyridin-3-yl) oxy)cyclohexane-1-carboxylic acid 287

1H NMR (500 MHz DMSO- d6) δ 7.98 (d, J = 8.54 Hz, 1H), 7.61 (d, J = 8.85Hz, 1H), 5.66 (s, 2H), 4.84 (br s, 1H), 4.54 (d, J = 2.75 Hz, 2H), 4.11(s, 3H), 3.91 (s, 1H), 2.73-2.92 (m, 1H), 2.65 (br s, 3H), 2.56 (s, 1H),1.24-2.12 (m, 17H) LCMS, [M + H]+ = 502.3 hLPA1 IC₅₀ = 118 nM Example268 (1S,3S)-3-((6-(5- (((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3- triazol-4-yl)-2-(methoxymethyl)pyridin-3-yl)oxy)cyclohexane-1- carboxylic acid 288

1H NMR (500 MHz, CDCl₃) δ 8.12 (br d, J = 8.53 Hz, 1H), 7.95 (br s, 1H),5.39-5.59 (m, 2H), 4.87 (br s, 1H), 4.20 (br s, 3H), 3.23 (br s, 2H),2.84 (br s, 1H), 2.68-2.79 (m, 3H), 1.46-2.19 (m, 10H), 0.88 (br s, 3H)LCMS, [M + H]+ = 449.1 hLPA1 IC₅₀ = 29 nM Example  93(1S,3S)-3-((2-methyl-6-(1- methyl-5-((((methyl-d3)(propyl)carbamoyl)oxy)methyl)-1H-1,2,3- triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 289

1H NMR (500 MHz, DMSO- d6) δ 8.29 (d, J = 8.85 Hz, 1H), 7.98 (br d, J =9.16 Hz, 1H), 5.45-5.65 (m, 2H), 4.99 (br s, 1H), 4.12 (s, 3H),2.91-3.14 (m, 2H), 2.83 (br s, 3H), 2.56- 2.69 (m, 1H), 1.41-2.04 (m,8H), 0.71-1.03 (m, 1H), −0.08- 0.50 (m, 4H) LCMS, [M + H]+ = 469.1 hLPA1IC₅₀ = 40 nM Example 270 (1S,3S)-3-((2-cyano-6-(5-((((cyclopropylmethyl)(methyl) carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid290

¹H NMR (500 MHz, DMSO- d₆) δ 8.30 (br s, 1H), 7.92 (br d, J = 9.77 Hz,1H), 6.91-7.38 (m, 5H), 5.47-5.72 (m, 2H), 5.00 (br s, 1H), 4.25-4.50(m, 3H), 3.94-4.20 (m, 2H), 2.60-2.88 (m, 4H), 1.37-2.18 (m, 8H) LCMS,[M + H]+ = 505.3 hLPA1 IC₅₀ = 2 nM Example 270 (1S,3S)-3-((6-(5-(((benzyl(methyl)carbamoyl)oxy) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-cyanopyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 291

1H NMR (500 MHz, DMSO- d6) δ 8.30 (br d, J = 8.85 Hz, 1H), 7.98 (d, J =9.16 Hz, 1H), 5.40-5.65 (m, 2H), 5.00 (br s, 1H), 4.13 (br s, 3H), 2.99-3.29 (m, 2H), 2.70-2.83 (m, 3H), 2.62 (br t, J = 9.92 Hz, 1H), 0.59-2.17(m, 15H) LCMS, [M + H]+ = 471.3 hLPA1 IC₅₀ = 15 nM Example 270(1S,3S)-3-((6-(5- (((butyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol- 4-yl)-2-cyanopyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 292

1H NMR (500 MHz, DMSO- d6) δ 8.24-8.45 (m, 1H), 8.30 (br d, J = 8.67 Hz,1H), 7.97 (br d, J = 9.09 Hz, 1H), 5.43- 5.68 (m, 2H), 5.01 (br s, 1H),4.05-4.22 (m, 3H), 3.56 (br s, 1H), 3.05-3.30 (m, 2H), 2.66- 2.83 (m,3H), 1.09-2.37 (m, 15H) LCMS, [M + H]+ = 483.2 hLPA1 IC₅₀ = 20 nMExample 270 (1S,3S)-3-((2-cyano-6-(5- ((((cyclobutylmethyl)(methyl)carbamoyl)oxy)methyl)-1-methyl- 1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 293

1H NMR (500 MHz, DMSO- d6) δ 8.30 (d, J = 9.16 Hz, 1H), 7.97 (br d, J =9.16 Hz, 1H), 5.52 (br s, 2H), 5.00 (br s, 1H), 4.12 (s, 3H), 3.40-3.67(m, 1H), 2.74 (br s, 3H), 2.57- (m, 1H), 1.29-2.22 (m, 14H) LCMS, [M +H]+ = 469.3 hLPA1 IC₅₀ = 23 nM Example 270 (1S,3S)-3-((2-cyano-6-(5-(((cyclobutyl(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3- yl)oxy)cyclohexane-1-carboxylic acid 294

1H NMR (500 MHz, DMSO- d6) δ 8.29 (d, J = 8.85 Hz, 1H), 7.97 (br d, J =9.16 Hz, 1H), 5.52 (br s, 2H), 5.00 (br s, 1H), 4.12 (s, 3H), 3.50-3.69(m, 1H), 2.65 (br s, 3H), 2.60 (br s, 1H), 1.22-2.11 (m, 16H) LCMS, [M +H]+ = 483.3 hLPA1 IC₅₀ = 15 nM Example 270 (1S,3S)-3-((2-cyano-6-(5-(((cyclopentyl(methyl)carbamoyl) oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy) cyclohexane-l-carboxylic acid

What is claimed is:
 1. A compound of Formula (X):

wherein R₂₀ is independently C₁₋₆ alkyl or H; R₂₁ is independently C₁₋₆alkyl or H; and X⁵ and X⁶ are independently CH or N.